Search

The causes of mental handicap are highly variable and involve both genetic and environmental factors. Approximately half of the cases have a familial origin, and in 50% of these the genetic defect can be linked to the X chromosome.1 This group of X linked mental retardation patients comprises patients in whom the mental handicap is associated with other clinical features (syndromic or specific mental retardation), and patients in whom the mental deficit is the only consistent clinical or morphogenetic manifestation (non-specific mental retardation, MRX). So far, the molecular basis of MRX is poorly understood because of the extreme genetic heterogeneity of this disorder. Fourteen MRX genes have been identified over the last few years, but each of these account for only a minor fraction of all cases. Since the causative mutation has been identified in only approximately 17% of families,2 it can be estimated that up to 100 MRX genes exist. Most of the currently known MRX genes were identified through the study of microscopically visible X chromosomal abnormalities: OPHN1 , TM4SF2 , ARHGEF6 , and ZNF41 by positional cloning of chromosomal translocation breakpoints,3–6 and FMR2 , IL1RAPL1 , and FACL4 by chromosome deletion mapping.7–9 In addition, disease related genomic deletions have been identified in other MRX genes and in genes associated with numerous other X linked conditions. In our laboratory, four X chromosomal genes associated with a human disorder have been identified based on deletion mapping: REP-1 in choroideremia,10 NDP in Norrie disease,11 POU3F4 in deafness type 3,12 and RPS6KA6 in mental retardation.13 Deletion mapping, however, is a time consuming method, and standard cytogenetic techniques have a limited resolution of approximately 5–10 Mb. It is a common belief that a number of deletions remain below the detection limit of …

Triple-A syndrome (MIM 231550) is an autosomal recessive disorder characterised by adrenocorticotrophin hormone resistant adrenal insufficiency, achalasia of the oesophageal cardia, and alacrima.1 The gene, previously localised to chromosome 12q13,2,3 was recently identified and denoted as AAAS .4 Among the five homozygous truncating mutations that were characterised, a single splice donor splice mutation (IVS14+1G→A) was found in several unrelated affected individuals of north African origin, strongly suggesting a founder effect.4 In this work, we were interested in estimating the time at which the mutation occurred, since this is expected to provide interesting and helpful information on its natural history. Different methods have been proposed to estimate the age of mutations,5,6 which are based either on allele frequencies7 or on intra-allelic variability and the pattern of linkage disequilibrium at closely linked marker loci8,9 with extensions to the analysis of multilocus data.9–12 However, these latter approaches are dedicated more to the fine mapping of the mutation, and may not be appropriate for estimating the age of rare mutant alleles that are only found in very few affected individuals. Therefore, we developed a new simple method based on likelihood that uses multilocus marker data to estimate the age of the most recent common ancestor of the mutation from a small number of patients. The method was tested through simulations and then applied to nine consanguineous Triple-A patients, who were homozygous for the IVS14+1G→A mutation. ### Method of dating We will first describe the principle of the method for two affected individuals who carry the studied mutation at the disease locus D , and then extend the method to a sample of N affected individuals. The basic assumption is that the two affected individuals descend from a common ancestor who introduced the mutation n gen generations …

The cone–rod dystrophies (CORDs) are a clinically and genetically heterogeneous group of progressive retinal disorders. They have similarities to the rod–cone or retinitis pigmentosa-type dystrophies, but can usually be distinguished on the basis of clinical findings and electrophysiology. The CORDs usually present with cone dysfunction related symptoms, including photophobia, poor colour vision, and reduced central visual function, but with time, poor night vision develops, reflecting rod photoreceptor involvement. The age of onset in the CORDs is variable, but most patients present in the first 2 decades of life. CORD is usually an isolated finding; less commonly it may be associated with other systemic abnormalities, including dental anomalies. The CORD syndromes in which the causative gene or chromosomal locus has been identified are shown in table 1. View this table: Table 1 Syndromic cone–rod dystrophies (CORDs) with identified genes and known chromosomal loci The association of CORD with amelogenesis imperfecta (AI) has been reported only once previously, in a large consanguineous Arabic family from the Gaza strip.12 AI is an inherited group of disorders of tooth enamel deposition affecting enamel structure, composition, and thickness, and can be broadly divided into the primarily hypoplastic (quantitative defect with thin or missing areas of enamel but otherwise normal in structure) and hypomineralised/hypomature (qualitative defect of normal thickness enamel but poorly mineralised) variants. However a new classification based on the molecular basis of the observed enamel phenotype will help to clarify the overlap in phenotypes that is commonly seen.13 The disorder in the Arabic family mapped to a 2 cM (5 Mb) region on chromosome 2q11, which includes the CNGA3 gene that encodes the α-subunit of the cGMP gated cation channel in cone photoreceptors.1 This represented a good candidate gene for this disorder because mutations in CNGA3 are associated with the cone dysfunction syndrome achromatopsia and with …

Squamous cell carcinoma of the head and neck, including the larynx, pharynx, and oral cavity, is a relatively common human neoplasm and accounts for approximately 2% of deaths from cancer in the western world.1 In 1985, there were nearly 900 000 new cases of head and neck cancer registered worldwide.1 An increasing number of epidemiological studies indicate that tobacco and alcohol consumption are major aetiological factors increasing the risk of developing head and neck cancer.2–4 The risk of head and neck cancer in smokers and alcohol users is more than twice that in non-smokers and non-alcohol users.5–7 The enzymes involved in these carcinogens’ metabolism have thus received a reasonable level of attention. Glutathione S-transferase (GST) M1 and T1 are two of a GST family which is involved in conjugation and detoxification reactions during the phase II metabolism of electrophilic compounds, including environmental carcinogens.8 Both of them have had a great deal of attention as possible genetic susceptibility factors for head and neck cancer. The GSTM1 gene is located on chromosome 1 (1p13.3), while the GSTT1 gene exists on chromosome 22 (22q11.2).8 Both of them are polymorphic. The GSTM1*0 (GSTM1 deficiency) and GSTT1*0 (GSTT1 deficiency) allele represent a deletion of the GSTM1 and GSTT1 gene and result in a loss of enzymatic activity.9 This suggested that individuals who lack these genes are more likely to develop cancer than those who have these genes, because of their inability to detoxify carcinogenic chemicals.5,10 GSTM1 and GSTT1 deficiency as risk factors for head and neck cancer were first reported in the middle 1990s.11,12 Since then, a number of studies have confirmed or refuted an association between GSTM1 or GSTT1 deficiency and head and neck cancer.4,6,7,11–41 These …

Hirschsprung disease (HSCR), a clinically complex syndrome often associated with a combination of mental retardation, microcephaly, and characteristic facial features, is genetically heterogeneous.1–10 Recently, mutations in ZFHX1B , which encodes Smad-interacting protein 1 (SIP1), were identified by our group11 and Cacheux et al 12 in patients with t(2;13)(q22;q22) and t(2;11)(q22.2;q21), respectively. These patients had clinical profiles consistent with a dominant form of the disease (Mowat-Wilson syndrome: MIM 235730).9,13 These and subsequent articles have demonstrated a link between patients with nonsense and frameshift mutations of the gene and the presence in these patients of the following clinical findings: profound mental retardation, delayed motor development, and specific facial features, including hypertelorism, a broad nasal bridge, strabismus, a pointed chin, prognathism, a nose with a prominent columella, and posteriorly rotated ears. Often associated with these features were microcephaly, epilepsy, congenital heart disease, HSCR, and midline defects such as agenesis or hypoplasia of the corpus callosum and hypospadias.13–19 This variety of clinical features is observed not only in patients with nonsense and frameshift mutations but also in patients harbouring deletions involving ZFHX1B at 2q22,9,11,15,20 including a previously reported isolated case.6 Thus, ZFHX1B clearly plays a critical role in the manifestation of clinical features of Mowat-Wilson syndrome. However, several points remain to be elucidated: (1) How broad are the clinical features in patients with ZFHX1B mutations and deletions? (2) What are the underlying molecular mechanisms by which the deletion of ZFHX1B at 2q22 affects the clinical phenotype? (3) What kind of clinical features might appear if the deletions were extended to include 2q23–q24.1? To address these questions, we have characterized the clinical features and underlying molecular basis of 27 cases with mutations or deletions in ZFHX1B , including 12 previously reported cases comprising …

Opitz syndrome (G/BBB syndrome, MIM145410 and MIM300000) is a midline congenital malformation characterised by hypertelorism, hypospadias and oesophagolaryngotracheal defects leading to swallowing difficulties and a hoarse cry.1 Additional defects include cleft lip with or without cleft palate, imperforate anus, anomalies of the central nervous system (including corpus callosum agenesis or vermis agenesis and hypoplasia),2 congenital heart defects (atrial and ventricular septal defects, patent ductus arteriosus and coarctation of the aorta),3 and developmental delay in two thirds of patients. This condition is genetically heterogeneous with an X-linked recessive form mapped to Xp22.3 and at least one autosomal dominant form mapped to chromosome 22q11.2.4 Also, several patients with an autosomal Opitz syndrome have been reported with a 22q11 deletion.5,6 Recently, mutations in MID1 , a member of the B-box protein family have been identified in the X-linked form of the disease7 but the gene for the autosomal dominant form on 22q11 remains unknown. MID1 encodes a protein belonging to a novel subclass of RING, B-box, Coiled-Coil proteins characterised by a fibronectin type III motif and a C-terminal domain. Although the function of MID1 remains unknown, recent experiments have demonstrated that MID1 is a microtubule associated protein, belonging to a large multiprotein complex8,9 involved in ubiquitination through microtubules.10 MID1 association with microtubules is regulated by dynamic phosphorylation involving MAP kinase and protein phosphatase 2A that is targeted specifically to MID1 by a regulatory α4 subunit. Here, we report on six MID1 mutations in a cohort of 14 patients with Opitz syndrome and on heart and hindbrain expression of MID1 during early human development using mRNA in situ hybridisation. In addition, we investigate the contribution of chromosome X-inactivation studies to identify the X-linked form of the disease. ### Patients A total of 14 cases were included …

Motor neurone disease includes a heterogeneous group of disorders with motor neurone involvement, such as amyotrophic lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, and primary lateral sclerosis. Amyotrophic lateral sclerosis is the most common adult onset form of motor neurone disease and involves the lower and upper motor neurones. It is characterised by progressive muscle weakness and atrophy, with fasciculations associated with hyperreflexia and spasticity. One of the proposed mechanisms for amyotrophic lateral sclerosis is degeneration of the motor neurone because of abnormal levels of toxic products that accumulate in the cell. Death usually occurs by respiratory failure about 2–3 years after the first symptoms.1 About 10% of cases are familial amyotrophic lateral sclerosis, and several loci have been associated with this disease. To date, the only two genes identified have been the zinc–copper superoxide dismutase 1 ( SOD1 ) gene, which is located on chromosome 21 (ALS1, MIM105400), and the Alsin gene, which is located at 2q33 (ALS2, MIM 205100).2–4 Autosomal dominant forms of amyotrophic lateral sclerosis also have been linked to 18q21 (ALS3, MIM 606640), 9q34 (ALS4, MIM 602433), and 15q15.1–q21.1 (ALS5, MIM 602099) and amyotrophic lateral sclerosis–frontotemporal dementia (MIM 105550) to 9q21-22.5–9 Moreover, mutations in Dynein are associated with motor neurone degeneration and defects in retrograde transport. This gene acts in the cellular division, trafficking, and transport of several proteins, such as SOD1 .10,11 More recently, two new loci have been associated with amyotrophic lateral sclerosis. One of them, reported by three independent groups, is on chromosome 16; the other is at 20p.12–14 We report a Caucasian Brazilian family with 26 members distributed in three generations affected by a late onset autosomal dominant motor neurone disease. Clinical and neurological examination of 11 living members was compatible with the diagnosis …

3 Diabetes mellitus or carbohydrate intolerance is frequently described. 1 The age of onset is variable. The disease usually comes at puberty but several cases have become symptomatic after 40 years. 4 The mole- cular defect that occurs in Friedreich's ataxia is the trinucleotide GAA expansion in the first intron of the X25 gene. This gene encodes for a 210 aa mitochondrial protein called frataxin. 5 Levels of frataxin mRNA and protein are severely reduced as a result of this expansion. 5 Although the exact physiological function of frataxin is not known, its involvement in iron-sulphur (Fe-S) cluster biogenesis 6 has been suggested. The Friedreich's ataxia phenotype shows a variable expression with respect to the age of onset and the presence of some signs or symptoms. Disease duration has been proposed to influence dysarthria, decreased vibration sense, optic atrophy, and diabetes. 7 Some Friedreich's ataxia phenotype features are strongly correlated with GAA expan- sion size. An inverse relationship has been demonstrated between GAA repeat size and the age of onset. 78 Friedreich's ataxia with retained reflexes or absence of cardiomyopathy was associated with shorter expansions. In a previous report, we demonstrated that GAA size accounts for about 70% of the onset age variance, 8

Fetal cells are consistently found in the maternal circulation, and polymerase chain reaction based studies have led to the identification of cell free fetal DNA (fetal DNA) in maternal blood. Approximately 1.2 nucleated fetal cells/ml of whole blood from women carrying a male fetus were detectable,1 and relative enrichment of fetal DNA was detected in the maternal plasma and serum.2 The amount of fetal DNA in the maternal blood increases with progression of pregnancy, and 3.4–6.2% of the total maternal plasma DNA during pregnancy was of fetal origin.3 Therefore, cell free fetal DNA in pregnant women’s plasma is useful for non-invasive prenatal diagnosis, especially for detection of fetal sex,3,4 RhD blood type,5–7 and gene mutations of paternal origin.8–10 Previous studies indicated that pregnant women with pre-eclampsia,11 placenta previa12 and fetal chromosome abnormalities13 tend to have elevated levels of fetal DNA in their plasma. Since functional or structural abnormalities of the placenta and destruction of the trophoblast may be associated with these diseases,14 it is suggested that cell free fetal DNA is of placental origin. This implies that quantitative analysis of fetal DNA may be valuable to screen for placental dysfunction. Ng et al15 recently reported that placental mRNA is present in the maternal circulation, and suggested that the same might occur for placental DNA,16 However, no direct evidence has been given for placenta derived cell free fetal DNA in the maternal blood, although its clinical use is growing.17 Confined placental mosaicism, which is defined by the presence of abnormal karyotypes only in the placenta while the fetus itself is usually diploid,18 may occur through a loss of the extra chromosome in a trisomic zygote during an early mitotic cell division in only the …

Recently, two studies1,2 reported independent evidence of genetic association between a 3′ UTR single nucleotide polymorphism (SNP; rs1050283 , also known as “+1073”) in the oxidised LDL receptor 1 gene ( OLR1 ) on chromosome 12p13.2 and risk for Alzheimer’s disease (AD). The implied chromosomal area is a highly promising AD candidate region because both genetic linkage and association studies have reported significant signals to two different locations separated by about 40 Mb (about 44 cM): the more proximal region is located near 10 Mb, on 12p13, and contains OLR1 as well as the gene encoding α2-macroglobulin ( A2M ), while the more distal region near 50 Mb, on 12q13, maps close to the genes encoding LRP1 (low density lipoprotein-related protein 1) and TFCP2 (transcription factor CP2). All four of these genes have shown independent associations with AD risk, although the results for A2M and LRP1 have been controversial (for recent reviews see Bertram and Tanzi3 and Saunders et al 4). For OLR1 , Luedecking-Zimmer and colleagues first reported evidence of association with the 3′ UTR SNP ( rs1050283 ) in a white North American case-control sample of more than 1500 subjects.1 This association showed a strong interaction with APOE (apolipoprotein E) e4-genotype, and led to opposite effects in subgroups stratified by APOE e4. Specifically, APOE e4-positive carriers of the TT-genotype had a 1.7-fold increased AD risk, whereas APOE e4-negative carriers of the same genotype showed a significantly reduced (OR = 0.7) risk for AD. Performing electrophoretic mobility shift assays (EMSAs) indicated reduced binding of nuclear proteins related to the T-allele of this variant. The more recently published results by Lambert et al were obtained on a large French case-control sample and a considerably smaller North American family-based sample, and also showed significant effects with this polymorphism.2 However, no APOE e4-dependence was …

and those by us 4 were only familial isolated congenital anosmia. Other cases of familial congenital anosmia had some additional manifestations 5-9 or had Kallmann syndrome. The defective smelling in isolated congenital anosmia may be attributed to the absence of olfactory function—that is, either replacement of the olfactory epithelium by respiratory epithelium, 2 or aplasia of the olfactory bulbs, sulci, and tract. 1 Diagnosis of isolated congenital anosmia is made by one or more of history, physical examinations, a standardised smelling test, com- puted tomography, magnetic resonance imaging, and biopsy of the nasal mucous tissue. Patients with isolated congenital anosmia had been unable to smell as back as they could remember, and had no history of other causes of anosmia, such as significant head trauma, neoplasm involving the olfactory system, or upper respiratory infection leading to damage of the olfactory epithelium. Physical examinations are useful to exclude an association of anosmia with other symptoms and to exclude secondary anosmia. A standardised smelling test confirms complete olfactory dysfunction. Computed tomography and magnetic resonance imaging may disclose other anomalies of the central nervous system, and biopsy may show abnormal replacement of the olfactory epithelium. An autosomal dominant mode of inheritance was suggested in a family reported by Lygonis 3 and two families by us. 4 However, nothing has been known for the disease gene localisation. Here we report the result of a genome-wide linkage analysis of the two unrelated Iranian families.

Distal spinal muscular atrophy (DSMA, OMIM #182960),1 also known as distal hereditary motor neuronopathy (DHMN),2 Charcot-Marie-Tooth (CMT) spinal type,3 and neuronal motor neuropathy of peroneal muscular atrophy4,5 include a heterogeneous group of disorders. The primary defect responsible for these conditions lies in the lower motor neurone, with distal involvement of only lower or both lower and upper limbs. DSMA is genetically heterogeneous. Four autosomal dominant and three autosomal recessive forms of the disease have already been mapped, including the Jerash type DHMN and congenital DSMA (table 1). However, the responsible genes were identified for only two of them: the glycil tRNA synthetase gene for DSMA type 56 and the immunoglobolin μ-binding protein 2 gene ( IGHMBP2 ) for DSMA type 6.7 View this table: Table 1 Mapped loci and identified genes for distal spinal muscular atrophy conditions (DSMA) Although pedigrees with isolated male patients have been described,3 no confirmed X linked form has been reported to date. We examined a white Brazilian genealogy with 17 male patients who present a distal form of muscular atrophy affecting upper and lower limbs. The pedigree is consistent with recessive X linked inheritance. We present results of neurological and diagnostic tests in nine affected patients, which are consistent with the diagnosis of DSMA, in accordance with the criteria established in the Second European Neuromuscular Consortium.8 Genetic linkage analysis allowed mapping of the disease locus to Xq13–Xq21. ### Patients The pedigree is depicted in fig 1. Nine affected males were examined. Diagnosis of DSMA was based on neurological examination and supported by electrophysiological and histopathological studies, according to the aforementioned guidelines.8 All studies were performed following informed consent. Figure 1 Family pedigree. The individuals who had their DNA analysed are underlined. ### Eletrophysiological studies In all affected patients, sensory nerve conduction studies were performed in the median, ulnar, superficial …

Primary ciliary dyskinesia (PCD; Immotile cilia syndrome; OMIM 242650) is an autosomal recessive disorder resulting from dysmotility of cilia and sperm flagella.1 Cilia and flagella function either to create circulation of fluid over a stationary cell surface or to propel a cell through fluid.2,3 These related structures are highly complex organelles composed of over 200 different polypeptides.4,5 The core or axoneme of cilia and flagella comprises a bundle of microtubules and many associated proteins. The microtubules are formed from α and β tubulin protofilaments and are arranged in a well recognised ‘9+2’ pattern: nine peripheral microtubule doublets in a ring connected around a central pair of microtubules by radial spoke proteins. The peripheral microtubules have dynein motor proteins attached and are connected with each other by nexin links.6–8 In human beings, ciliated epithelium can be found lining the respiratory tract, including the sinuses and middle ear, the brain ependyma, the female oviduct, and the male vas deferens. Cilia in the respiratory tract play an important part in airway clearance of respiratory secretions. In primary ciliary dyskinesia, impaired mucociliary clearance causes recurrent respiratory tract infections including chronic otitis media, rhinitis, and sinusitus, often leading to permanent lung damage (bronchiectasis).9 Patients are also often subfertile due to sperm tail immotility and immotile oviduct cilia. About half of the patients have defects of laterality, usually complete mirror-image reversal of the left-right axis (situs inversus) and this association is known as Kartagener syndrome (OMIM 244400). The defects in left-right axis determination associated with primary ciliary dyskinesia are proposed to result from dysfunction of the embryonic node monocilia during development.10–12 Primary ciliary dyskinesia has an incidence of 1 in 20 000 with enrichment in certain populations.9,13 Diagnosis is made on brushings or biopsy …

The F form of acropectorovertebral dysgenesis, also called F syndrome, is a rare dominantly inherited fully penetrant skeletal disorder.1 The name of the syndrome is derived from the first letter of the surname of the family in which it was originally described. Major anomalies include carpal synostoses, malformation of first and second fingers with frequent syndactyly between these digits, hypoplasia and dysgenesis of metatarsal bones with invariable synostosis of the proximal portions of the fourth and fifth metatarsals, variable degrees of duplication of distal portions of preaxial toes, extensive webbing between adjacent toes, prominence of the sternum with variable pectus excavatum and spina bifida occulta of L3 or S1. Affected individuals also have minor craniofacial anomalies and moderate impairment of performance on psychometric tests.3 Two families have been reported to date. The condition was first described by Grosse1 in eight members of a four generation American family of European origin. Camera4 presented an Italian family with two affected relatives and a very similar phenotype, suggesting the diagnosis of F syndrome. Recently, Dundar et al2 reported a six generation Turkish family with an acropectoral-like condition showing some phenotypic overlap with F syndrome. Affected individuals have soft tissue syndactyly of all fingers and toes and, to a variable degree, pre-axial polydactyly of hands and feet. The condition was mapped to chromosome region 7q36. Here we report that the F syndrome family originally described by Grosse et al1 maps to chromosome region 2q36 and is thus distinct from the acropectoral syndrome published by Dundar et al.2 At the time of the original study in 1968,1 the F family consisted of four generations of affected and unaffected persons. A fifth generation born since then includes an affected female and two affected males. A total of nine …

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of disorders that involve the peripheral nervous system.1 It is characterised by progressive distal neurogenic muscular atrophy and weakness that initially affects the peroneal muscles and later the hands. Charcot-Marie-Tooth disease type 1 (CMT1), also called hereditary motor and sensory neuropathy type I (HMSN I), is a dominantly inherited demyelinating neuropathy characterised by reduced nerve conduction velocities (NCV) (motor median NCV

Cleft lip and/or cleft palate is among the most frequent birth defect seen in humans, with a reported prevalence of 1 in 700 births worldwide.1 Development of the secondary palate is a complex coordinated sequence of events, beginning with the appearance of palatal shelves from the first branchial arch derived maxillary prominences during the sixth week of embryogenesis. This involves mesenchymal–epithelial interactions, cell differentiation, migration, and transformation, with the interactive role of soluble growth factors, extracellular matrix molecules and their receptors, and programmed cell death.2,3 A disruption anywhere in the required sequence may result in a failure of the palate to close. A genetic involvement in clefts was first recognised by Fogh-Anderson,4 with the majority of cases thought to display a multifactorial mode of inheritance.5 Analysis of recurrence risk patterns of cleft lip with or without cleft palate (CL/P) indicates that there are likely to be few major loci interacting epistatically with an oligogenic background.6,7 As a consequence, there have been numerous studies to identify genetic determinants, either studying individual candidate genes and loci,8,9 or screening at the whole genome level.10–12 These efforts have been encouraged by the many candidates revealed by mouse mutants that exhibit a cleft as at least part of their phenotype.13 Nevertheless, the results of many of these studies have not been informative, with only a few candidate genes or loci being strongly implicated in human CL/P or CP only.12 As a consequence, the mechanisms of interaction, which probably include both genes and the environment, remain poorly understood. Recently, however, significant progress has been made with the identification of gene mutations in several forms of CL/P and CP. These include the cell adhesion molecule PVRL1 14 and the transcription factors MSX1 , IRF6 …

The formation of intracellular amyloid-like inclusions by mutant proteins is a feature of two groups of codon reiteration diseases, for which there are currently no treatments. The first group that was described includes the nine known neurodegenerative conditions caused by polyglutamine (polyQ) repeat expansions resulting from CAG trinucleotide repeat mutations, exemplified by Huntington’s disease (HD).1 HD is caused by a tract of more than 37 uninterrupted polyglutamines in exon 1 of the HD gene product, huntingtin. Genetic and transgenic studies are consistent with a model where expanded polyglutamines cause disease by conferring a novel toxic function on the disease proteins.1–3 The second type of codon reiteration mutation results in autosomal dominant oculopharyngeal muscular dystrophy (OPMD).4 OPMD is caused by the abnormal expansion of a (GCG)n trinucleotide repeat in the coding region of the polyadenine binding protein 2 gene ( PABP2 ): a (GCG)6 repeat is expanded to (GCG)8–13 in most patients. In some rare cases, insertion mutations such as (GCG)6GCA(GCG)2, (GCG)6GCA(GCG)3 and (GCG)6(GCA)3(GCG)2 are seen.5,6 In PABP2 , (GCG)6 codes for the first six alanines in a homopolymeric stretch of 10 alanines. Thus, disease is associated with expansions of 12 or more uninterrupted alanines in this nuclear protein. OPMD is characterised by aggregates in muscle cell nuclei comprising mutant PABP2 as a major component.4,7–9 The role of inclusions in these diseases has been vigorously disputed.1 Nevertheless, strategies that target protein misfolding frequently reduce aggregate formation and cell death in parallel. In mammalian cell based models of both polyglutamine and polyalanine diseases, the mutant proteins are much more prone to aggregate formation than their wild-type counterparts and cause significantly more cell death.10,11 In such models, …

In hereditary non-polyposis colorectal cancer (HNPCC), the most common form of inherited colorectal cancer, detection of the causal alteration of the mismatch repair ( MMR ) gene involved is essential for proper management of the families. This will allow the identification of relatives with high risk for colorectal or endometrial cancer, who require the appropriate screening and, conversely, will avert useless surveillance in non-carrier relatives. Mutational studies,1 based on conventional screening methods, have indicated that point mutations of MSH2 , MLH1 , or MSH6 can be detected in approximately 55% of the families, fulfilling the Amsterdam (AMS) criteria. These stipulate: In a recent study, we showed that genomic rearrangements of MSH2 are involved in approximately 20% of the AMS+ HNPCC families without detectable point mutations within MSH2 or MLH1 .3 This study was performed using quantitative multiplex PCR of short fluorescent fragments (QMPSF), which can easily detect heterozygous genomic deletions and duplications.3–7 This method is based on the simultaneous amplification of short genomic sequences under quantitative conditions, using dye labelled primers, and the superimposition of the electropherograms of patients and controls. ### Key points

Alternating hemiplegia of childhood (AHC, MIM 104290) is a rare syndrome, characterised by early onset of episodic hemi- or quadriplegia lasting minutes to days. This disorder, first reported by Verret and Steel in 1971,1 has historically been thought to represent a migraine equivalent1 or an unusual form of epilepsy or a movement disorder,2 as it typically presents with complex and variable clinical features. In most patients, the earliest manifestations clearly related to AHC are tonic–dystonic attacks and paroxysmal nystagmus associated with autonomic changes and paroxysmal dyspnoea and usually appear between 3 and 6 months of age. The hemiplegic episodes develop before 18 months of age lasting anywhere from minutes to days at a time and involving either side of the body or shifting from one side to the other during the same episode with a period of bilateral weakness when the second side becomes involved.3 Some attacks are characterised by a bilateral involvement, which is apparent from the beginning, and do not follow an hemiplegic episode,3 which determines extreme hypotonia of the whole body with inability to move and a level of consciousness markedly depressed. A characteristic feature of AHC is the disappearance of all abnormalities when the child falls asleep.3 With increasing age, hemiplegic episodes follow a general pattern of initially increasing frequency and duration, followed by a plateau, and finally by a decrease in the number and duration of attacks. Analogously, the paroxysmal manifestations associated with hemiplegia tend to decrease in frequency and intensity with time and usually disappear after 5–7 years. Development before the onset of hemiplegic episodes may be normal or delayed. Epileptic seizures are reported in a variable percentage of sporadic patients.3–5 An association with migraine has also been noticed since the earliest description.1 Indeed, for …

Data from twin, family, and adoption studies provide strong evidence that genetic factors play a major aetiological role in schizophrenia. By a series of linkage studies, chromosome 8p has been implicated as a region harbouring a schizophrenia susceptibility gene.1–4 Recently, Stefansson and colleagues reported that neuregulin 1 (NRG1 ), located in 8p21-12, may be involved in the aetiology of schizophrenia.4,5 In their linkage and association studies, a 290 kb core at risk haplotype at the 5′ end of NRG1 was found to be strongly associated with schizophrenia in Icelandic and Scottish populations. This haplotype contains the first exon of NRG1 , which encodes a part of glial growth factor 2 ( GGF2 ). Deficiency of glial growth factors has been presumed to be implicated in the pathogenesis of schizophrenia.6 Futhermore, NRG1 mutant mice have fewer functional N-methyl D-aspartate(NMDA) receptors than wild type mice, and display stereotypic behavioural abnormalities similar to those of normal mice treated with the psychogenic drug phenylcyclidine.4 This core at risk haplotype was defined by five single nucleotide polymorphisms (SNP8NRG221132, SNP8NRG221533, SNP8NRG241930, SNP8NRG243177, SNP8NRG433E1006) and two microsatellites (478B14-848, 420M91395). The frequency of this haplotype in schizophrenic individuals was higher than in controls; in Icelandic samples the frequency was 15.4 (7.5%; p = 0.000087).4 The first replication using Scottish samples revealed a similar result at 10.2 (5.9%; p = 0.00031).5 Another replication performed by Williams et al with British or Irish samples used one SNP and the two microsatellites of the core at risk haplotype. However, the association was much weaker at 9.5 (7.5%; p = 0.04).7 Yang et al reported other markers located in the middle of NRG1 and associated with schizophrenia, in a Chinese population.8 Another independent analysis using 13 microsatellites found two groups of haplotypes, which were significantly …

Apolipoprotein E (apoE) is a protein involved in the transport and metabolism of plasma cholesterol and triglycerides. The apolipoprotein E gene (APOE), located at chromosome 19q13.2, has three major alleles called e2, e3, and e4, defined by two single nucleotide polymorphisms (SNP) located in exon 4 at positions 3937 (T/C) and 4075 (C/T). The corresponding apoE isoforms differ at amino acid positions 112 (Cys for apoE2 and apoE3, Arg for apoE4) and 158 (Arg for apoE3 and apoE4, Cys for apoE2), and have been shown to have different functional and biochemical properties.1–4 APOE polymorphisms have been studied in relation to several genetic diseases and disorders. The APOE e4 allele has been associated with an increased risk of Alzheimer’s disease, coronary heart disease, and death after myocardial infarction.5–7 Conversely, the APOE e2 allele was found to have a protective effect on the occurrence of Alzheimer’s disease. However, in other studies, APOE e2 was associated with an increased risk of cardiovascular diseases and with some blood lipid abnormalities.8,9 It has been reported recently that APOE e2 homozygote children from Ghana became infected with Plasmodium falciparum at an earlier age than those carrying other APOE genotypes.10 In this study, performed in the Gambia, the APOE e2, e3, and e4 allele distributions were analysed in children with mild (338 cases) or severe (530 cases) malaria, and in individually matched control children (560 subjects). Additionally, the APOE Th1/E47 polymorphism located in the APOE promoter region11 was studied in a subset of children consisting of 183 severe malaria cases and 179 controls. ### Study subjects Between August 1989 and September 1990, 1428 children aged from 1 to 10 years were enrolled at the Royal Victoria Hospital of Banjul and at the Medical Research Council Hospital of Fajara, in the Gambia. Malaria …

X-linked mental retardation (XLMR) has a prevalence of 2.6 cases per 1000 population, accounting for over 10% of all cases of mental retardation. Clinically, XLMR exists in syndromic (MRXS) and non-syndromic (MRX) forms, that is without other distinguishing features. Non-syndromic X-linked mental retardation (MRX) is a highly heterogeneous group of conditions in which mental retardation (MR) is the only consistent clinical feature in patients. This in contrast to syndromic forms of X-linked mental retardation (MRXS), where MR is associated with recognisable clinical signs such as congenital malformations, neurological features, or metabolic disturbances. Identifying novel genes that are responsible for MRX is difficult due to the heterogeneity of this disorder. At present 30 genes have been identified as playing a role in MRXS. However in MRX, only 15 genes are known to be involved accounting for less than one-fifth of all MRX.1–6 The recent observations that RSK2, MECP2 , and ARX play a role in both syndromic and non-syndromic forms of XLMR,7–10 suggest that a molecular basis to strictly separate these two forms is not always present. In addition, careful clinical re-examination of patients with an OPHN1 gene mutation has revealed distinctive phenotypic hallmarks, such as cerebellar hypoplasia, in patients who were previously classified as non-syndromic.11,12 The frequency of causative mutations in any of the 15 MRX genes known today appears to be very low, so in the majority of patients with MRX the genetic cause is still not known. It has been suggested that up to 100 different genes might be involved in MRX.1–4 Seven of the 15 genes have been cloned on the basis of their disruption by chromosomal rearrangements in mentally retarded patients. Recently, it has been predicted that approximately 30% of all mutations underlying MRX are located in the …

The insulin-like growth factors (IGFs; somatomedins) comprise a family of peptides that play important roles in mammalian growth and development. The principal members of this family are IGF1 and IGF2. IGF1 (somatomedin C), a 70 residue basic polypeptide, mediates many of the growth promoting actions of growth hormone (GH) and has metabolic and mitogenic effects.1 The major source of circulating IGF1 is the liver, but it is also produced in a wide variety of tissues and has endocrine and paracrine modes of action. The mature IGF1 peptide has A, B, C, and D domains with homology to insulin, and is highly conserved.2 It is produced as an inactive precursor, pre-pro-IGF1, with an additional carboxyterminal E region that plays an important role in the maturation of normal IGF1 peptide. This regulatory region is obtained by alternative splicing of the last two exons. IGF1 resides on the long arm of chromosome 12 (12q 22–24.1),3 and several molecular studies have demonstrated that the structure of this gene is very complex. The gene contains six exons, which extend over more than 85 kb on chromosomal DNA. For human IGF1, two potential primary translation products exist: IGF1A and IGF1B, with sizes of 153 and 195 amino acids respectively. The two precursors are synthesised from distinct messenger RNAs produced by alternative splicing of the primary transcript. IGF1A mRNA contains exons 1, 2, 3, 4, and 6 of the human IGF1 gene while IGF1B is encoded by exons 1, 2, 3, 4, and 5. It has been speculated that IGF1B plays the major role during intrauterine growth, while the same function during postnatal growth is taken over by IGF1A.4 Recent studies have focused attention on the genetic causes of growth alterations. Mutations involving the molecular structure of GH5 or the function of …

Prenatal diagnosis of syndromes caused by chromosomal abnormality is a long established part of obstetric care in developed countries. In this area, there have been recent significant advances in the identification of high risk pregnancies using sophisticated serum analyte and ultrasound screening methods.1,2 For follow up diagnostic testing, karyotyping has provided the gold standard. This technology has remained essentially unchanged over 30 years, as no new technology has yet proven superior in terms of being able to detect such a wide range of abnormalities with the necessary precision. Nevertheless, molecular tests, such as fluorescent in situ hybridisation (FISH) 3 and short tandem repeat analysis,4 are now in common practice for the diagnosis of specific abnormalities. These adjunctive tests importantly decrease turnaround times from 1–2 weeks to 1–2 days. We assessed the performance of multiplex ligation dependent probe amplification (MLPA) as an alternative method for the detection of aneuploidy, which is by far the most common prenatal chromosome abnormality. This novel technique5 detects sequence dosage differences in a semi-quantitative manner and has many potential applications in diagnostic molecular genetics and cytogenetics. For example, a recent report describes its use for detection of large genomic deletions and duplications in the BRCA1 gene.6 This technology appears to have significant advantages in that it is extremely versatile in its applications, flexible in its target loci, highly automated, suitable for high throughput testing, efficient, and cost effective. Its application for aneuploidy detection has not been reported in a clinical setting. In order to assess the precision and robustness of the test, we conducted a prospective blind trial on 492 consecutive amniocentesis samples referred to our cytogenetics laboratory. ### Study design This study was designed to blind test amniocentesis samples prospectively. The samples were collected over a 4 month period as they were referred …

Approximately 1 in 1000 children is born with a serious permanent hearing impairment (pre-lingual deafness), and it is estimated that more than half of these cases in developed countries are due to genetic factors.1–3 The prevalence of hearing loss increases dramatically with age; it is estimated that approximately 5% of people under 45 years of age have a significant loss of hearing, increasing to approximately 50% by 80 years of age.1 Age related late onset hearing loss (presbycusis) is a heterogeneous trait with many suspected causes.4 Genetic or environmental factors such as diabetes, mitochondrial mutations, or environmental noise exposure may contribute to the trait. In addition, hearing loss beginning at late childhood, youth, or later, clearly segregates as a monogenic autosomal dominant Mendelian trait in many families. The hearing loss phenotype in these families is usually non-syndromic—that is, the hearing loss is not associated with other anomalies, and it accounts for up to 20% of the cases of non-syndromic sensorineural inherited deafness. This type of hearing loss is usually progressive, affecting a particular range of frequencies in each case.5 To date, 36 loci for autosomal dominant non-syndromic sensorineural hearing loss (ADNSSHL) have been mapped, and 17 deafness genes from these loci have been identified.6 These genes encode a wide variety of proteins; some have known function but for most, the underlying mechanisms leading to hearing impairment are uncertain. Given the few described mouse models for progressive hearing loss,7 our current understanding of post-lingual and progressive deafness relies on the identification of genes through human mapping studies. In this work we describe the mapping of a novel DFNA locus on chromosome 1q21–q23 segregating in a Spanish family with post-lingual and progressive hearing loss. ### Family data We ascertained a four generation family (S277) segregating ADNSSHL, through the …

Primary open angle glaucomas (POAGs) are the commonest form of glaucoma among Caucasians. They are defined by an excavation of the optic nerve head, a progressive loss of the visual field, and a normally open iridocorneal angle.1 Their prevalence is 1–2% and they are a major cause of irreversible blindness in Western countries.2 Albeit not necessary to the definition of POAG, an elevation of intraocular pressure (IOP) is a major contributory factor, and its lowering is at present the only available therapeutic strategy. In a subset of POAG patients, however, the IOP remains in the normal range—that is, less than 21 mm Hg, defining normal tension glaucoma (NTG).3 Whether NTG constitutes a pathological entity distinct from POAG is debated.4 Genetic factors play a major role in POAG predisposition. The genetic basis of POAG, is complex and heterogeneous.5 Recently, the OPTINEURIN (OPTN) gene on chromosome 10p14 was shown to be implicated in NTG.6 Mutations in this gene were found to segregate in nine out of 54 families with dominantly inherited POAG and normal or moderately elevated IOP. A variant, M98K, was associated with an increased absolute risk of 13.6% in a group of 169 POAG patients with normal or elevated IOP, compared with a relative allele frequency of 2.1% in a control population.6 This observation has made the M98K variant the potentially most important single genetic factor contributing to POAG predisposition. It is therefore essential to assess its role in different populations. In the present study, we evaluated the M98K variant in two groups of POAG patients, one from France and the other from Morocco, with population matched controls. Participants gave their informed consent, in keeping with European legislation and following a protocol reviewed and approved by supporting institutions. Both groups, 237 subjects from …

Mitochondrial disorders are clinical phenotypes associated with abnormalities of the terminal component of mitochondrial energy metabolism—that is, oxidative phosphorylation. Oxidative phosphorylation is carried out in the inner mitochondrial membrane by the four enzyme complexes (I–IV), of the respiratory chain plus the adenosine triphosphate (ATP) synthase complex (complex V). All these complexes, except complex II, which is entirely nucleus encoded, contain both nucleus and mitochondrion encoded subunits, and their biosynthesis also requires co-operation between the nuclear and mitochondrial genomes. Because of this dual genetic control, oxidative phosphorylation diseases can be due to mutations either in mitochondrial DNA (mtDNA) or nuclear DNA genes. Pathogenic mutations of mitochondrial DNA include either large scale rearrangements, which are usually sporadic, or point mutations and micro-rearrangements, which are usually transmitted through the maternal lineage. However, these concepts have recently been challenged by the identification of one family in which a de novo microdeletion in a mtDNA gene was detected in a patient’s mitochondrial genome, which had clearly been inherited from the proband’s father1 and of a family with a mother to offspring transmission of a single mtDNA deletion.2 We present here a case of maternal transmission of a single heteroplasmic deleted mtDNA species in two subjects, both affected by Kearns-Sayre syndrome (KSS). ### Patient 1 A woman with KSS (subject I-1 in fig 1A) died at 48 years of age of respiratory insufficiency. She was the second of four uneventful pregnancies from healthy non-consanguineous parents. At the age of 14 years, she noted the presence of bilateral eyelid ptosis and ophthalmoparesis. Over the following 4 years, both symptoms steadily progressed and she developed bilateral hearing loss, ataxia and proximal limb muscle weakness. At the age of 27 years, she received a heart pacemaker because of several brief episodes of unconsciousness, associated with atrioventricular block of variable severity, …

Peroxisome proliferator activated receptor-γ (PPAR-γ) is a transcription factor abundantly expressed in adipocytes, and plays a key role in the regulation of adipocyte differentiation, lipid storage, glucose homeostasis, and blood pressure.1 Several rare, dominant negative mutations have been detected in three families with severe insulin resistance, diabetes, and hypertension,2 while a rare, gain of function mutation has been detected in four unrelated individuals with extreme obesity.3 In addition, a meta-analysis based on data from over 3000 individuals has shown that a common polymorphism in the PPAR-γ gene has an influence on individual susceptibility to type 2 diabetes.4–8 Taken together, these findings indicate that rare, severe mutations of the PPAR-γ gene may cause extreme metabolic syndrome in a small number of patients, while common, mild variants of this gene may contribute to the common, multifactorial forms of these disorders. Systematic screening of the PPAR-γ gene for sequence variants has identified two common polymorphisms.9–11 These are, respectively, a C→G substitution in exon B resulting in the conversion of proline to alanine at residue 12 of the PPAR-γ protein, and a synonymous C→T substitution at nucleotide position 161 in exon 6.9–11 In this study, we examined these genetic variants in relation to body mass index (BMI) in a large cohort of white British patients with coronary artery disease (CAD), a disease closely related to obesity, dyslipidaemia, diabetes, and hypertension. A number of previous studies have examined the Pro12Ala polymorphism in relation to BMI;12 however, the results of these studies were not totally consistent. The disparate findings may be partly attributed to insufficient power in some studies. In addition, it has been suggested that the Pro12Ala polymorphism has an effect on BMI in individuals with marked obesity, and that this effect is not apparent …

Usher syndrome (USH) is an autosomal recessive disorder comprising of bilateral sensorineural hearing loss, progressive loss of vision due to retinitis pigmentosa (RP), and variable vestibular dysfunction. It is the most frequent cause of deafness and concurrent blindness in schools for the deaf-blind,1with a prevalence of 1/16 000 to 1/50 000 in various populations.2The majority of Usher syndrome cases can be clinically classified into three subtypes.3,4USH type I (USH1; OMIM 276900, 276903, 276904, 601067, 602097, 602083 and 606943) is characterised by profound prelingual sensorineural hearing loss, vestibular areflexia, and prepubertal onset of RP. USH type II (USH2; OMIM 276901, 276905 and 605472) is characterised by moderate to severe hearing impairment, no vestibular impairment, and onset of RP in the first or second decade of life. USH type III (USH3; OMIM 276902) is characterised by progressive, post-lingual hearing loss, variable onset and severity of RP, with or without vestibular dysfunction. Atypical forms of Usher syndrome associated with mutations in USH1B and USH1D have also been reported.5–7There is progression of hearing loss in some of these atypical cases, making them potentially difficult to clinically distinguish from USH3. USH3 was originally thought to be very rare, accounting for at most a few percent of the total USH population, until Pakarinen and coworkers found that up to 40% of the USH cases in Finland were consistent with USH3.4Difficulty in accurately detecting the progression of hearing loss may account for the lower frequency of reported USH3 cases outside of Finland. In the Finnish USH3 cohort, hearing loss was diagnosed before the age of 10 years in most patients, but up to the age of 40 years in some patients, with moderate to severe hearing threshold elevations at the time of detection. The mean …

Bipolar affective disorder (BPD), a common severe mood disorder characterised by manic and depressive episodes, has an estimated lifetime prevalence of 0.1%–1% in various populations, including that of Taiwan.1 Although previous studies have strongly suggested the involvement of genetic factors in the aetiology of BPD, the search for predisposing genes using classical linkage analysis has been fraught with difficulty. Association studies have been shown to be effective in mapping genes for complex diseases and have therefore been widely applied to studies of many psychiatric traits, including BPD.2,3 The results suggest that several genes with minor effects might be involved in the pathogenesis of BPD and that genes involved in neurotransmitter metabolism or signal transduction are possible candidates for an association with BPD.3–5 Serotonin (5-hydroxytryptamine; 5-HT), a major neurotransmitter in the central nervous system, is involved in various physiological events, such as mood control, sleep, thermoregulation, learning, and memory.6 Disruption of serotonergic function has been implicated in the pathogenesis of many psychiatric disorders, including BPD.7,8 Serotonin exerts its diverse functions through multiple receptor (HT receptor; HTR) subtypes.9 These receptors, localised on the post- or pre-synaptic neuronal membrane, bind released serotonin and either transmit the signal to the post-synaptic neurone or regulate serotonin production by the neurone itself. Seven classes of HTRs (HTR1–7), made up of 15 functionally and pharmacologically distinct receptor subtypes,10,11 have been identified in mammalian species in the past few years. Except for HTR3, which is a ligand gated ion channel receptor, all known HTR family members are guanine nucleotide binding protein (G-protein) coupled receptors. Of these 15 subtypes, several, which are abundantly expressed in the limbic system and have a high affinity for antipsychotic drugs, are related to mood control.12 Studies on knockout or transgenic mice …

The magnitude of the risk of prostate cancer among Ashkenazi Jewish carriers of the common mutations in the BRCA1 and BRCA2 genes, the so-called Ashkenazi BRCA founder mutations ( BRCA1 185delAG and 5382insC, and BRCA2 6174delT), remains uncertain. Two large epidemiological studies have suggested that the cumulative incidence of prostate cancer among male first degree relatives of individuals with a founder mutation may approach 30% by 80 years of age.1,2 Smaller clinical studies have, in general, not demonstrated an increased frequency of founder mutations among Jewish men with prostate cancer.3–6 Only one study to date has examined clinical characteristics of prostate cancer patients with founder mutations.3 In this study, the three BRCA associated tumours that were identified appeared to be associated with biologically more aggressive disease, presenting with higher PSA levels, higher Gleason scores and more advanced stage at diagnosis, than did prostate cancers diagnosed in men without mutations. Founder BRCA mutations occur in more than 2% of Ashkenazi Jews.1,7,8 Thus, an increased risk of prostate cancer among BRCA carriers, or an aggressive phenotype in BRCA associated prostate cancers, could constitute a significant cancer burden in this group, and would have substantial management implications for male carriers of Ashkenazi founder mutations. We undertook the current study to obtain a more stable estimate of the Ashkenazi founder mutation rate among Jewish men diagnosed with prostate cancer, and to determine if prostate cancer occurring in carriers of the common Ashkenazi BRCA1 or BRCA2 mutations is associated with distinctive pathological or clinical features. The precedent for this hypothesis is best illustrated by the hereditary renal cancer syndromes, in which recognising specific histological subsets of subjects has facilitated the identification of genetically distinct disorders.9,10 All men newly diagnosed with prostate cancer were identified at sixteen …

Neurofibromatosis 2 (NF2) is an autosomal dominant disease that is caused by inactivating mutations of the NF2 tumour suppressor gene.1,2 Multiple central and peripheral nervous system tumours and ocular abnormalities are common in NF2; bilateral vestibular schwannomas are pathognomonic for the disease. Genotype-phenotype correlations are well established for NF2 associated tumours. In general, constitutional nonsense or frameshift NF2 mutations are associated with severe NF2 (that is, earlier onset of symptoms and more tumours), splice site mutations with variable disease severity, and missense mutations with mild disease. Genotype-phenotype correlations have not been reported for the non-tumour manifestations of NF2. The most common of these manifestations is presenile cataracts, which occur in about 60–80% of people with NF2.3–5 In animal models, lens fibre cells that are more differentiated express less Nf2 protein than the epithelial regions of the lens, suggesting that the Nf2 protein may play a role in lens epithelial cell migration or elongation.6 The purpose of this study was to determine if there were genotype-phenotype correlations for cataracts in NF2. The study was based on the United Kingdom NF2 registry in the Department of Medical Genetics, St Mary’s Hospital, Manchester. NF2 patients are ascertained by contacting neurosurgeons, otolaryngologists, neurologists, paediatricians, dermatologists, and geneticists throughout the United Kingdom, augmented in the North West Region by the Regional Cancer Registry. The study was subject to continuing ethics committee evaluation and patients consented to participation. Patients were screened for constitutional NF2 mutations using single strand conformational polymorphism analysis (SSCP) as previously described,7 and examined for cataracts using slitlamp biomicroscopy at the time of diagnosis of NF2. For this study, cataracts were defined as present or absent (that is, posterior subcapsular cataracts and cortical cataracts were aggregated). There were 255 people from 190 families (159 people with new …

Congenital hearing loss occurs in approximately 1 in 1000 live births and 60% of these cases are hereditary.1,2 Non-syndromic autosomal recessive deafness accounts for about 70% of congenital hereditary hearing loss cases. To date, at least 33 genetic loci have been mapped for non-syndromic deafness, and the causative genes for 17 of these loci have been identified.3 Mutations in the TMPRSS3 gene, which encodes a transmembrane serine protease, were originally identified in Pakistani DFNB8 and Palestinian DFNB10 families, and later in two Tunisian families and several white patients.4–9 TMPRSS3 belongs to a family of transmembrane serine proteases, which includes TMPRSS1-5.5,10 Like the other members of this family, TMPRSS3 contains a short amino terminus, a transmembrane domain and a large extracellular or lumenal carboxyl terminal segment characterised by a stem region containing LDLRA (low density lipoprotein receptor class A), SRCR (scavenger receptor cysteine rich) domains, and a catalytic domain. In addition to a deleterious β-satellite repeat insertion and splice acceptor site substitution,6 six pathogenic missense mutations have been isolated.7 Since these mutations occur not only in the catalytic domain, but also in the LDLRA and SRCR domains involved in interactions with extracellular molecules, the molecular mechanism for pathogenesis is unclear. In this study, we determine whether these missense mutations affect the proteolytic activity of TMPRSS3. ### Key points

Cone-rod dystrophies (CRD) are forms of inherited retinal dystrophy which characteristically lead to early impairment of vision. An initial loss of colour vision (cone mediated functions) and of visual acuity, usually from the first or second decade of life, is followed by night blindness (largely rod mediated) and loss of peripheral visual fields.1 CRD patients suffer from severe photophobia and show reduced ERG responses. In later life, vision may be reduced to a bare perception of light. CRD is a milder condition compared to Leber congenital amaurosis (LCA) which is the most severe form of all the inherited retinal dystrophies and is diagnosed as bilateral congenital blindness, with a diminished or absent electroretinogram (ERG). Cone-rod dystrophy loci have been mapped to chromosomes 17q,2 19q,3 18q,4 17p13,5,6 6q,7 1q12,8 and 8p11.9 Mutations in the peripherin/RDS ,10 CRX ,11,12 and RetGC-I 13,14 genes have been shown to cause autosomal dominant CRD. Mutations in the ATP binding cassette transporter rim protein ( ABCR) gene have been shown to be associated with autosomal recessive CRD.15 Mutations in the CNGA3 gene encoding the α-subunit of the cone photoreceptor cGMP gated channel have also been reported to cause cone photoreceptor disorders.16 The RPGRIP1 protein (retinitis pigmentosa GTPase regulator interacting protein 1, MIM 605446) is encoded by the gene located on chromosome 14q11. It consists of 24 exons and the predicted size of its protein product is 1259 amino acids. It is expressed specifically in the rod and cone photoreceptors and is a structural component of the ciliary axoneme. One of its functions is to anchor the RPGR protein within the photoreceptor connecting cilium.17 Recently, in an in vivo investigation of RPGRIP1 function and its physical interaction, it has been shown that …

A newborn whose weight for gestational age and sex is less than expected, based on population standards, is considered as having intrauterine growth restriction (IUGR); a cut off at less than the 10th centile is often used to define IUGR. Causes of IUGR remain unclear although a number of fetal and maternal risk factors have been identified.1,2 Increased early morbidity and mortality, as well as, possibly, less than optimal neuropsychological development, have been reported as consequences of IUGR.2,3 In addition, small size at birth has been associated with health problems in adulthood such as coronary heart disease and dyslipidaemia.4,5 The association between restricted fetal growth and adult chronic diseases (often referred to as the Barker hypothesis) is now considered robust and possibly causal.6 Apolipoprotein E (apoE) is one of the key regulators of plasma lipid levels as it affects hepatic binding, uptake, and catabolism of several classes of lipoproteins.7 The apolipoprotein E gene (APOE) codes for the apoE protein; in animal models, underexpression of the APOE gene and lack of the apoE protein result in increased susceptibility to atherosclerosis,8,9 whereas gene overexpression displays anti-inflammatory, antiproliferative, and atheroprotective properties.10 ApoE has also emerged as a central factor in various biological processes such as immunoregulation, control of cell growth and differentiation,11 and brain development.12 The three common allelic variants at the APOE locus (e2, e3, e4) code for three major apoE protein isoforms (E2, E3, E4). These isoforms differ from one another only by single amino acid substitutions, yet these changes exhibit functional consequences at both the cellular and molecular levels.13,14 In previous studies, children who carry the e4 allele and those who carry the e2 allele have been shown to have, respectively, higher and lower total …

Inherited hearing impairment is a highly heterogeneous group of disorders with an overall incidence of about 1 in 2000 newborns.1 In approximately 70% of cases, the auditory impairment is not associated with other clinical features, that is, it is non-syndromic. The most frequent condition is a severe or profound hearing loss of prelingual onset, which is inherited mainly as an autosomal recessive trait.1 To date, 31 different DFNB loci for autosomal recessive non-syndromic hearing loss have been reported, and 16 genes have been identified.2 Among these loci, DFNB1 in 13q12 stands out because of its complexity and clinical relevance. It contains the gene GJB2 , which encodes connexin26, a component of intercellular gap junctions. Mutations in the GJB2 gene are responsible for up to 50% of all cases of autosomal recessive hearing impairment in most of the populations tested so far, with a frequent mutation (35delG) accounting for up to 86% of the GJB2 mutant alleles in white populations.3,4 However, not all the DFNB1 mutations affect the GJB2 gene. Recently, several research teams found a deletion in the 13q12 region which is frequently inherited in double heterozygosity with mutant GJB2 alleles in affected subjects,5–7 but it was also found in homozygosity.6,7 Molecular characterisation of this deletion, termed del( GJB6 -D13S1830), showed that it encompasses 342 kb and it does not affect the GJB2 gene, but it truncates the gene encoding connexin30 ( GJB6 ), another gap junction protein expressed in the inner ear.6 The existence of this deletion was first suspected by the finding of inconsistencies in the segregation of genetic markers distal to GJB2 . ### Key points

We report a Jordanian Arab family where two sibs developed the classical clinical and radiological features of pantothenate kinase associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz disease) but in addition had an early onset cerebellar ataxia.1,2 Using polymorphic microsatellite markers we have shown that this family is not linked to the pantothenate kinase gene ( PANK2 ) on chromosome 20.2 We hypothesise that the disorder, Karak syndrome, is novel and a member of the growing family of neurological diseases involving excess cerebral iron accumulation, for example, PKAN, neuroferritinopathy, aceruloplasminaemia, and Friedreich’s ataxia.2–6 Both affected members (fig 1, IV.1 and IV.2) were the product of a normal pregnancy and birth and had normal developmental milestones and progress at school until disease onset at the age of 6 years. They developed an ataxic gait that was slowly progressive, and was associated with decreased school performance. At 8 years of age they developed inverted feet (calcaneovarus), which was associated with frequent falls. Around the age of 9 years, both started to have choreiform movements of all four limbs, more marked in the upper limbs than in the lower limbs. By the age of 10 years the condition had progressed and they were unable to walk without assistance, and they left school soon after. Their mother found difficulty in feeding them because of swallowing problems after the age of 10 years and they were unable to dress, bathe, or feed themselves by their mid-teens. There were no visual or auditory symptoms or history of epilepsy. Both parents and four older sibs, two brothers and two sisters, were in good health. The parents were first cousins and came from an inbred family (fig 1). The family lived in Karak, a town in southern Jordan. Figure 1 A simplified pedigree of the research family. Affected …

Cleft palate (CP) is one of the most common congenital malformations. It can occur as part of a recognisable syndrome, associated with other malformations or, most commonly, be non-syndromic (CPO) (MIM 119540). The birth prevalence of CPO varies between and among populations but it is seen world wide. The highest incidence has been found in Finland, 1.01 per 1000 livebirths.1 Within Finland, there are regional differences in birth prevalence; the Oulu region (in northern central Finland) and central western Finland are over-represented, with up to twice the incidence compared to the average.1 Differences are even more striking when analysing the birth places of the grandparents of probands.1 The gene defects or susceptibility genes for clefts remain largely unknown and the basic mechanism causing the failure of the secondary palate to close is still poorly understood. Extrinsic factors like advanced paternal age, maternal smoking, and overall intake of medicines during the first trimester have been suggested to increase the risk of CPO.2 Although some pedigrees have shown autosomal dominant and X linked recessive inheritance, the risk of recurrence for relatives in large series of cases differs greatly from expected values calculated on the basis of a simple Mendelian mode of inheritance. Targeted mutations in mice have shown that malfunction of very different types of genes can lead to cleft palate, msx1 and tgfb3 among them.3–5 In humans, defects in genes encoding collagens,6 a fibroblast growth factor receptor,7 a sulphate transporter,8,9 a nucleolar protein,10 and a thyroid transcription factor11 have appeared to be associated with syndromes where cleft palate can be involved. For non-syndromic cleft palate, neither mutations nor linkage to a specific chromosomal region has yet been established. However, linkage disequilibrium was suggested in two studies between MSX1 and …

Plasma lipid concentrations are complex traits having both environmental and genetic determinants. About half of the variation in HDL-C and TG may be genetic1–3 with the same genes possibly accounting for the correlated traits of LDL particle size, TG, and HDL-C.4 A number of variants in candidate genes have been implicated in the regulation of plasma lipid levels.5 In addition, genome scans have identified chromosomal regions with suggestive linkage to the TG:HDL-C ratio and other lipid parameters.6,7 Nonetheless, much of the genetic variability in HDL-C and TG levels remains unexplained. Decreased HDL cholesterol (HDL-C) and raised triglyceride (TG) levels are well known risk factors for the development of coronary artery disease (CAD) and atherosclerosis.8 Plasma TG and HDL-C levels are highly correlated, but there is some evidence that they may exert independent effects on coronary disease risk.9 Indeed, the simultaneous use of both may more accurately predict risk of coronary disease. Among patients with low HDL-C, risk of CAD was more than doubled in those with concurrent high TG compared to those with low TG levels in both the PROCAM10 and Helsinki Heart studies.11 Furthermore, the ratio of TG:HDL-C has been shown to correlate with LDL particle size12 and is a powerful predictor of future myocardial infarction.13 The scavenger receptor class B type 1, SR-B1, is a key component in the reverse cholesterol transport pathway where it binds HDL-C with high affinity and is involved in the selective transfer of lipids from HDL-C.14,15 It is expressed primarily in liver and non-placental steroidogenic tissues and mediates selective cholesterol uptake by a mechanism distinct from the classical low density lipoprotein cholesterol (LDL-C) receptor pathway.16 Previous studies17,18 have found single nucleotide polymorphisms (SNPs) in the gene …

Costello syndrome (CS) is characterised by postnatal growth retardation, relative macrocephaly, distinctive facies, loose, hyperpigmented skin with deep palmar and plantar creases, and developmental delay.1–4 Cutaneous papillomata, which when present are the hallmark of this syndrome, develop in childhood. Cardiac anomalies, either structural defects, hypertrophic cardiomyopathy, or tachyarrhythmia, are present in 60% of cases.5 The cause of CS is unknown. Segregation analysis and recognition of advanced paternal age support autosomal dominant inheritance, with most cases being the result of de novo mutations.6 For uncommon conditions such as CS, which are generally sporadic, gene identification often relies upon clinical observation or rare cases with chromosomal rearrangements. A single translocation has been described in CS, t(1;22)(q25;q11).7 Recently, malignant tumours have been reported in a significant number of patients with CS, suggesting that a predisposition to malignancy is part of the condition. Bladder carcinoma has been reported twice.8,9 Three patients developed ganglioneuroblastomas.10,11 There have been single reports of epithelioma12 and vestibular schwannoma.13 However, rhabdomyosarcoma (RMS) has been reported in 10 patients.14–18 In seven of these cases, the tumour histology was embryonal; one was pleomorphic, one of unknown subtype,18 and the other alveolar.15 Based on the published cases of CS, with and without tumours, a tumour frequency as high as 17% has been suggested.18 We hypothesise that the increased malignancy risk in CS is the result of involvement of a tumour suppressor gene in the causation of CS, either by deletion or mutation. We suggest that the predisposition to malignancy occurs when a second mutation in the tumour suppressor gene occurs. Demonstration of loss of heterozygosity (LOH) is a proven technique for localisation of tumour suppressor genes. We report here the outcome of LOH and candidate gene studies …

We looked for pathogenic MECP2 mutations in 11 families with an index case affected by Rett syndrome (RTT), together with a sib or other relative affected by RTT or a less specific developmental disturbance. In one family, we detected the same MECP2 mutation in two affected sisters and their unaffected mother, who was subsequently shown to have skewed X chromosome inactivation. In five families, one affected subject was found to have a MECP2 mutation, but the other relative in whom a diagnosis of RTT was suspected, did not carry this or any other detectable MECP2 mutation. In the remaining five families, no MECP2 mutation was detected in any subject. These results suggest that familial RTT is rare and may be overdiagnosed. Furthermore, and despite the small probability of recurrence, many relatives of females with the usual, sporadic RTT may seek genetic testing to clarify their situation. Rett syndrome (RTT) is a neurodevelopmental disorder that mostly affects females and is usually sporadic. It has therefore often been considered to be an X linked dominant condition with male lethality, although it is now recognised that de novo mutations in RTT occur predominantly on the paternally derived X chromosome and this could lead to similar observations.1–4 It is an important cause of profound mental handicap in girls, accounting for up to 10% of all cases. The diagnosis is currently based upon the clinical criteria proposed by the Rett Syndrome Working Group in 1988.5 The major criteria are: (1) normal pre- and perinatal period and apparently normal development for the first 6 months of life, (2) a period of regression occurring at 6 months to 3 years of age, (3) deceleration in head growth, (4) acquisition of stereotypical hand movements, and (5) eventual profound developmental delay. In addition, there are a …

Copper dependency in humans is most dramatically illustrated in Menkes disease, an X linked recessive copper deficiency disorder that is generally lethal in early childhood.1,2 Menkes disease is caused by mutations in a transmembrane copper transporting P type ATPase, MNK (or ATP7A), which is expressed in virtually all non-hepatic tissues.3–5 Studies using cultured cells suggest that MNK is located in the trans-Golgi network (TGN), where it transports copper to copper dependent enzymes synthesised within secretory compartments.6–8 In addition to this biosynthetic role, MNK functions in the efflux of excess copper from cells via a process of copper stimulated trafficking to the plasma membrane.6,9 Copper export via MNK from intestinal enterocytes is essential for supplying the blood with dietary copper. Similarly, MNK mediated copper export from the capillary endothelium of the blood brain barrier is thought to supply copper to the central nervous system. In Menkes patients, these processes are defective resulting in a range of symptoms attributable to deficiencies in copper dependent metabolism. These include neurological degeneration, mental retardation, seizures, arterial and bone abnormalities, hypothermia, and hypopigmentation.2 Classical Menkes disease rapidly progresses and is generally lethal during early childhood, although milder variants of the disease exist.10,11 The treatment of Menkes disease involves parenteral injections of copper-histidine, which in the most successful cases reduces neurological defects and prolongs life expectancy.2,12,13 This copper replacement therapy bypasses the intestinal blockage of dietary copper absorption and increases circulating copper levels. However, to prevent the onset of neurological symptoms in Menkes patients, copper must be delivered across the endothelial cells of the blood brain barrier to supply copper to the central nervous system. Within the central nervous system, copper transport into secretory compartments of neurones and other cells to supply copper …

Ageing is associated with chronic, low grade inflammatory activity leading to long term tissue damage, and systemic chronic inflammation has been found to be related to mortality risk from all causes in older persons.1 Also, the genetic constitution of the organism interacting with systemic inflammation may cause defined organ specific illnesses. Thus, age related diseases such as Alzheimer’s disease (AD), Parkinson’s disease, atherosclerosis, type 2 diabetes, sarcopenia, and osteoporosis, are initiated or worsened by systemic inflammation, suggesting the critical importance of unregulated systemic inflammation in the shortening of survival in humans.1–3 Accordingly, proinflammatory cytokines are believed to play a pathogenetic role in age related diseases, and genetic variations located within their promoter regions have been shown to influence the susceptibility to age related diseases, by increasing gene transcription and therefore cytokine production.3,4 Conversely, genetic variations determining increased production of anti-inflammatory cytokines or decreased production of proinflammatory cytokines have been shown to be associated with successful ageing, suggesting a role for the control of the inflammatory state in the attainment of longevity. As recently reported, the distribution of +874T→A interferon(IFN)-γ,5 −174C→G IL-6,6 and −1082G→A interleukin(IL)-107 single nucleotide polymorphisms (SNPs) has been shown to be different in centenarians than in younger people.5–7 The +874T allele, involved in high production of the proinflammatory cytokine IFN-γ, was found less frequently in centenarian women than in control women.5 Also, the proportion of subjects homozygous for the G allele at the −174 IL-6 locus, characterised by high serum levels of the proinflammatory cytokine IL-6, was significantly decreased in centenarian men.6 Conversely, the presence of the −1082 GG genotype, suggested to be associated with high production of the anti-inflammatory cytokine IL-10, was significantly increased in centenarian men in comparison with younger male subjects.7 These …

Obesity is a symptom of diagnostic value in multiple congenital anomaly-mental retardation syndromes. While acquired non-specific weight gain related to drug intake or associated behavioural disorders occasionally occurs in the course of mental retardation, obesity is known to be a specific feature of several well defined conditions, including Bardet-Biedl syndrome, Prader-Willi syndrome, Cohen syndrome, fragile X syndrome, and several chromosomal anomalies. Yet a number of mentally retarded children with apparently early onset weight gain remain undiagnosed. Here, we report on a de novo deletion of chromosome 9q34 in two unrelated mentally retarded children with early onset obesity, distinctive facial features (brachycephaly, synophrys, anteverted nostrils, prognathism), sleep disturbances, and behavioural problems. FISH and microsatellite DNA analyses showed that the two children carried a similar small deletion (3 Mb) of the terminal long arm of chromosome 9 (del 9q34). We suggest therefore that the del 9q34 is a novel cause of syndromic obesity and mental retardation. Its association with distinctive facial features and behavioural problems should help in recognising this novel phenotype. Based on this observation, we suggest giving consideration to cryptic deletions of chromosome 9q34 in the diagnosis of unexplained obesity/mental retardation syndromes ### Case 1 A boy was born to unrelated, healthy parents after a term pregnancy and normal delivery (birth weight 3200 g, length 50 cm, OFC 34.5 cm). He was hypotonic in the first months of life but no feeding difficulties were originally noted. Excessive weight gain with increased appetite and food seeking behaviour were noted at 30 months of age. At 5 years, his weight was 26 kg (>+3 SD), length 112 cm (+1 SD), and OFC 48 cm (−2 SD) and at 9 years his weight was 72 kg (>+ 6 SD), length 144 cm (+2 SD), and OFC 52.5 cm (−0.5 SD) (figs 1A–C and 2A). Distinctive facial …

Neurofibromatosis type 1 (NF1) and type 2 both occur in mosaic (segmental) forms.1 When NF1 (and other autosomal dominant skin disorders)1,2 occurs in a linear, patchy, quadrant, or otherwise localised form, two different types of mosaicism can be distinguished.2 Type 1 segmental involvement reflects heterozygosity for a postzygotic mutation occurring in an otherwise healthy embryo. The segmental lesions are limited to the affected area and show the same degree of severity as that found in the corresponding non-mosaic trait (for example, mosaic/segmental NF1). Type 2 segmental involvement occurs in a heterozygous embryo and reflects loss of heterozygosity that occurred at an early developmental stage. Clinically, the lesions of type 2 segmental involvement are markedly more pronounced and superimposed on a milder, non-segmental, heterozygous manifestation of the same trait.2 In the light of these concepts of mosaicism, we critically reviewed (previously published) antique illustrations of presumed “full blown” NF1 sufferers.3–9 We have diagnosed as having mosaic/segmental NF1 the Indian man (“ Homuncio ”) in the “ Monstrorum Historia ”10 of the Italian naturalist and philosopher Ulisse Aldrovandi (1522-1605), the horned monster in “ Des Monstres et Prodiges ”11 of the French surgeon Ambroise Pare (1510-1590), and the goitred woman in the “ Buch der Natur ”12 of the German naturalist Conrad von Megenberg (1303-1374). Type 2 segmental manifestations of NF1 were recognisable in Buffon’s girl (1707-1788)13 and the “Wart Man” of Tilesius (1793).14 ### Key points

Opsismodysplasia ( opsismos in Greek = late) is a rare chondrodysplasia, first described in 1977 by Zonana et al 1 as a unique chondrodysplasia and designated “opsismodysplasia” only in 1984.2 The disorder is characterised clinically by micromelia with extremely short hands and feet and respiratory distress responsible for death in the first few years of life.2 The main radiological features include severe platyspondyly, major delay in skeletal ossification, and metaphyseal cupping. To date, 13 cases have been reported and recurrence in sibs and/or consanguinity have suggested an autosomal recessive mode of inheritance.1–6 Here, we describe the clinical, radiological and chondro-osseous findings of 12 previously unreported cases in nine families. We show that opsismodysplasia is not a consistently lethal condition and we identify the severity of the delayed bone ossification as an important feature, distinct from other forms of spondylo(epi)metaphyseal dysplasias. Seven male and five female cases originating from nine families of French (4/9), German, (1/9), and Algerian origin (4/9) were included in the study. All affected cases presented with the following inclusion criteria: (1) major delay in epiphyseal ossification, (2) platyspondyly, (3) metaphyseal cupping, and (4) very short metacarpals and phalanges. Half of the cases were prenatally diagnosed during ultrasound follow up of the pregnancies and half of them were diagnosed postnatally. Pregnancies were terminated between 15 and 29 weeks’ of gestation. For chondro-osseous studies, the samples were embedded in paraffin and HES routinely stained after fixation in 4% formaldehyde and decalcification with EDTA. ### Key points

Genetic disorders of the skeleton or skeletal dysplasias are a clinically diverse and genetically heterogeneous group of connective tissue disorders affecting skeletal morphogenesis and development.1–4 More than 200 different entities have been described.5 Despite the growing availability of molecular testing for several of these disorders, the diagnosis of a skeletal dysplasia still relies primarily on a thorough clinical and radiographic study of the patient.6 Some particular radiographic signs can be very helpful in establishing the diagnosis. One such example is the presence of cone shaped epiphyses.7 In most instances, cone shaped epiphyses represent the initial stage of premature epimetaphyseal fusion resulting in growth arrest and shortening of the bone involved. Analysis of the site and shape of cone shaped epiphyses, in particular of the phalanges, can be helpful in the diagnosis of skeletal dysplasias.8–10 Based on the observation of four patients, we delineate a new skeletal dysplasia with autosomal recessive inheritance. Because all cases show cone shaped epiphyses in the hands and a radiographically characteristic involvement of the proximal femoral epiphyses, we propose naming this condition acrocapitofemoral dysplasia. ### Patient 1 Patient 1 was referred at the age of 9.5 years with the tentative diagnosis of hypochondroplasia. She was born at 34 weeks’ gestation with a birth weight of 2470 g (50th centile) and length of 47 cm (50th-90th centile). The pregnancy was uncomplicated and the delivery uneventful. Around the age of 7 years, short stature was noted. She had normal psychomotor development but experienced emotional problems related to her short stature. The parents are healthy but consanguineous (fig 1A). The father measures 166 cm and the mother 163 cm. A younger sister is also healthy and has a normal height. Physical examination at the age of 9 years 6 months showed short stature with height …

We originally identified the IL1RAPL1 gene through its partial deletion in a patient with Becker muscular dystrophy (BMD), glycerol kinase deficiency (GKD), adrenal hypoplasia congenita (AHC), and mild mental retardation,1 and suggested that its disruption might account for the patient’s cognitive problems. Other workers have shown that intragenic mutations of the IL1RAPL1 gene are associated with mild, non-specific X linked mental retardation.2 IL1RAPL1 encodes a putative transmembrane cytokine receptor related to receptors and receptor accessory proteins for interleukin-1 and -18, and is expressed in brain and muscle.3 The protein structure comprises three extracellular immunoglobulin domains, which presumably mediate binding of an as yet unidentified ligand, a transmembrane region, and an intracellular domain, which is likely to enable signalling via the NFκB pathway. Its role in brain development or function is not understood. We describe here the precise structure of a complex deletion-inversion-deletion mutation involving more than 2 Mb of Xp21 in a patient with a contiguous gene deletion syndrome. This results in the loss of several genes and the creation of an unusual fusion of the IL1RAPL1 and dystrophin genes with the potential to generate a chimeric protein product. We discuss the possible mutational mechanisms and biological consequences of this rearrangement. ### Clinical description The patient was the second child of healthy, non-consanguineous parents (father 39 years old, mother 17). He was well in the immediate neonatal period, but collapsed at 17 hours with profound hypoglycaemia. In spite of intravenous dextrose, he had a cardiopulmonary arrest. Resuscitation required several doses of intravenous epinephrine and he eventually responded to intravenous hydrocortisone. Subsequently, he required artificial ventilation for four days. Following resuscitation, he was found to be hyponatraemic and ultrasound scanning failed to identify the adrenal glands. Further investigation showed glycerol kinase deficiency (0.3 nmol/h/mg protein in cultured skin fibroblasts), an undetectable …

The brachydactylies are a heterogeneous group of inherited digital abnormalities originally classified into five types, on the basis of malformation of the digits.1 Among them, brachydactyly type A1 (BDA-1, MIM 112500), also referred to as Farrabee or Fitch type 9, is mainly characterised by short middle phalanges, which may be fused to the terminal ones.1,2 All the small tubular bones tend to be reduced in size, but the middle phalanges are the most severely shortened. Several phenotypes have been described for this disease. BDA-1 may occur as an isolated condition or maybe associated with other manifestations. Patients often have short stature and additional features, such as radial and/or ulnar clinodactyly, malformed or absent epiphyses, scoliosis, abnormal menisci, and club feet.3,4 Some patients also showed mental retardation, nystagmus, squint, and sixth nerve palsy.5,6 Despite the fact that BDA-1 has been identified as a Mendelian disorder since 1903,7 until recently few molecular genetic studies on this malformation have been performed. Several candidate genes including MSX1 , MSX2, FGF1 , FGF2 , and the HOXD gene cluster have been excluded for this autosomal dominant disease.8 In 2000, a linkage study performed in two large Chinese families mapped the locus for BDA-1 to chromosome 2q35-q369 and subsequent analysis in the same families identified mutations in the Indian hedgehog gene ( IHH ) in affected subjects.10 The IHH gene lies within the critical region on chromosome 2q35-q36, and codes for a signalling molecule that is known to mediate condensation, growth, and differentiation of cartilage. To date, there have been no other reports linking IHH mutations to BDA-1. Moreover, the affected subjects who showed a mutation in the IHH gene had physical manifestations beyond those described in BDA-1 by Fitch,2 and a recent study in a …

Neurofibromatosis 2 (NF2) is a severe autosomal dominant disorder that predisposes to multiple tumours of the nervous system. About half of all patients are founders with clinically unaffected parents. The purpose of the present study was to examine the extent to which mosaicism is present in NF2 founders. A total of 233 NF2 founders with bilateral vestibular schwannomas (BVS) were screened by exon scanning. NF2 mutations were detected in the blood samples of 122 patients (52%). In 10 of the 122 cases, the ratio of mutant to normal alleles was obviously less than 1, suggesting mosaicism. Tumour specimens were available from 35 of the 111 subjects in whom no mutation could be detected in blood specimens. Mutational analysis by exon scanning detected typical NF2 mutations in 21 of the 35 tumours. In nine subjects, the alterations found in tumours could be confirmed to be the constitutional mutation based on finding of identical mutations in pathologically and/or anatomically distinct second tumours. In six other subjects with only a single tumour available, allelic loss of the NF2 gene was found in addition to the mutation in each tumour, suggesting that either the mutation or the deletion of the NF2 gene is probably the constitutional genetic alteration. Our results suggest that failure to find constitutional mutations in blood specimen from these 15 patients was not because of the limitation of the applied screening technique, but the lack of the mutations in their leucocytes, best explained by mosaicism. Extrapolating the rate (15/35 = 43%) of mosaicism in these 35 cases to the 111 NF2 founders with no constitutional NF2 mutations found in their blood, we inferred 48 mosaic subjects (111 x 0.429). Adding the 10 mosaic cases detected directly in blood specimens, we estimate the rate of mosaicism to be 24.8% (58/233) in our cohort of 233 NF2 founders with bilateral vestibular schwannomas.