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BACKGROUND: Inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) is a negative regulator of insulin signalling and has previously been found to be associated with hypertension, obesity and type 2 diabetes in a cohort of families with diabetes in the UK presenting features of metabolic syndrome. In particular, a haplotype of three genetic polymorphisms (rs2276047, rs9886 and an insertion/deletion polymorphism in intron 1) was found to be strongly associated with increased susceptibility to hypertension. OBJECTIVE AND METHODS: To assess if INPPL1 variants play a direct role in the development of essential hypertension, we genotyped the three previously associated INPPL1 polymorphisms in a cohort of 712 families with severe hypertension from the BRIGHT study transmission disequilibrium test cohort. RESULTS: We found no evidence of significant association between hypertension and any of the three INPPL1 polymorphisms or haplotypes (p>0.1). CONCLUSION: These results suggest that INPPL1 variants may be involved in mechanisms causing hypertension in metabolic syndrome patients specifically.

Aims: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9) , and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. Patients and methods: 409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single-strand conformational polymorphism (SSCP) (exons 3, 4, 6–10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP. Results: Mutations were detected in 253 (61.9%) patients: 236 (57.7%) carried LDLR , 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9 . After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels ( LDLR , PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL-C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL-C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03). Conclusions: The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.

Background: Recently the genotype/phenotype map of Wolf-Hirschhorn syndrome (WHS) has been refined, using small 4p deletions covering or flanking the critical region in patients showing only some of the WHS malformations. Accordingly, prenatal-onset growth retardation and failure to thrive have been found to result from haploinsufficiency for a 4p gene located between 0.4 and 1.3 Mb, whereas microcephaly results from haploinsufficiency of at least two different 4p regions, one of 2.2–2.38 Mb and a second one of 1.9–1.28 Mb. Methods and Results: We defined the deletion size of a ring chromosome (r(4)) in a girl with prenatal onset growth retardation, severe failure to thrive and true microcephaly but without the WHS facial gestalt and mental retardation. A high-resolution comparative genome hybridisation array revealed a 760 kb 4p terminal deletion. Conclusions: This case, together with a familial 4p deletion involving the distal 400 kb reported in normal women, may narrow the critical region for short stature on 4p to 360–760 kb. This region is also likely to contain a gene for microcephaly. “In silico” analysis of all genes within the critical region failed to reveal any strikingly suggestive expression pattern; all genes remain candidates for short stature and microcephaly.

Objective: The aim of this study was to determine if there is a significant difference in the risk of developing Wilms tumour between patients with submicroscopic and those with visible deletions of the WT1 tumour suppressor gene. Methods: To determine which subjects had WT1 deletions, high-resolution chromosomal deletion analysis of the 11p13 region was carried out in 193 people with aniridia. The rationale for this was that aniridia is caused by loss of function of one copy of the PAX6 gene, and although most patients with aniridia have intragenic mutations, a proportion has deletions that also include the nearby WT1 gene. Fluorescence in situ hybridisation (FISH) analysis of patients with aniridia identifies people with WT1 deletions regardless of whether they have Wilms tumour, allowing the deletion size to be correlated with clinical outcome. Results: Wilms tumour was not observed in any case without a WT1 deletion. Of subjects in whom WT1 was deleted, 77% with submicroscopic deletions (detectable only by high-resolution FISH analysis) presented with Wilms tumour compared with 42.5% with visible deletions (detectable by microscopy). This difference was significant. Conclusions: High-resolution deletion analysis is a useful tool for assessing the risk of Wilms tumour in neonates with aniridia. People with submicroscopic WT1 deletions have a significantly increased risk of Wilms tumour, and a high level of vigilance should be maintained in such cases.

Background: The cell surface glycoprotein, E-Cadherin (CDH1) is a key regulator of adhesive properties in epithelial cells. Germline mutations in CDH1 are well-established as the defects underlying the Hereditary Diffuse Gastric Cancer (HDGC)syndrome: an increased risk of lobular breast cancer (LBC) has been described in HDGC kindreds. However, germline CDH1 mutations have not been described in LBC patients outside of HDGC families. We sought to investigate the frequency of germline CDH1 mutations in LBC patients with early onset disease or family histories of breast cancer without DGC. Methods: Germline DNA was analyzed in 23 women with invasive lobular or mixed ductal and lobular breast cancers who had at least one close relative with breast cancer or had themselves been diagnosed before age 45, had tested negative for a germline BRCA1 or BRCA2 mutation, and reported no personal or family history of diffuse gastric cancer. The full coding sequence of CDH1 including splice junctions was PCR amplified and screened for mutations using DHPLC and sequencing. Results: A novel germline CDH1 truncating mutation in the extracellular portion of the protein (517insA) was identified in one subject who had lobular breast cancer at age 42 and a first degree relative with invasive lobular breast cancer. Conclusions: Germline CDH1 mutations can be associated with invasive lobular breast cancer in the absence of diffuse gastric cancer. The finding, if confirmed, may have implications for management of individuals at risk for this breast cancer subtype, and compels clarification of the cancer risks in the syndrome.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a congenital disorder characterised by growth retardation, facial dysmorphisms, skeletal abnormalities and mental retardation. Broad thumbs and halluces are the hallmarks of the syndrome. RSTS is associated with chromosomal rearrangements and mutations in the CREB-binding protein gene (CREBBP), also termed CBP, encoding the CREB-binding protein. Recently, it was shown that mutations in EP300, coding for the p300 protein, also cause RSTS. CBP and EP300 are highly homologous genes, which play important roles as global transcriptional coactivators. OBJECTIVE: To report the phenotype of the presently known patients with RSTS (n = 4) carrying germline mutations of EP300. RESULTS: The patients with EP300 mutations displayed the typical facial gestalt and malformation pattern compatible with the diagnosis of RSTS. However, three patients exhibited much milder skeletal findings on the hands and feet than typically observed in patients with RSTS. CONCLUSIONS: Part of the clinical variability in RSTS is explained by genetic heterogeneity. The diagnosis of RSTS must be expanded to include patients without broad thumbs or halluces

Background: During whole genome microarray-based comparative genomic hybridisation (array CGH) screening of subjects with idiopathic intellectual disability, we identified two unrelated individuals with a similar de novo interstitial microdeletion at 2p15-2p16.1. Both individuals share a similar clinical phenotype including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. Methods: Clinical assessments, and cytogenetic, array CGH and fluorescence in situ hybridisation (FISH) analyses were performed. Results: The microdeletions discovered in each individual measured 4.5 Mb and 5.7 Mb, spanning the chromosome 2p region from 57.2 to 61.7 Mb and from 56 to 61.7 Mb, respectively. Each deleted clone in this range demonstrated a dosage reduction from two to one copy in each proband except for clone RP11-79K21, which was present in three copies in each proband and in four copies in their respective parents (two per each chromosome 2 homologue). Discussion: The common constellation of features found in the two affected subjects indicates that they have a newly recognised microdeletion syndrome involving haploinsufficiency of one or more genes deleted within at least a 4.5-Mb segment of the 2p15-16.1 region.

Background: Autism is a common childhood neurodevelopmental disorder with suggested genetic background. About 5-10% of autism cases are associated with chromosomal abnormalities or monogenic disorders. However, the role of subtle genomic imbalances in autism has not been delineated. Here, we have tested a hypothesis suggesting autism to be associated with subtle genomic imbalances manifested as low-level chromosomal mosaicism. Methods: We surveyed stochastic (background) aneuploidy in children with/without autism by interphase three-colour fluorescence in situ hybridization (FISH). The rate of chromosome loss and gain involving six arbitrarily selected autosomes and sex chromosomes was assessed in peripheral blood cells of 60 unaffected children and 120 children with autism. Results: Four autistic boys from 120 analyzed (3.3%) with rare structural chromosomal abnormalities: 46,XY,t(1;6)(q42.1;q27); 46,XY,inv(2)(p11q13); 46,XY,der(6),ins(6;1)(q21;p13.3p22,1)pat; 46,XY,r(22)(p11q13) were excluded from further molecular cytogenetic analysis. Studying over 420,000 cells in 60 controls and 116 children with idiopathic autism, we have determined the mean frequency of stochastic aneuploidy in control and autism: (i) autosome loss - 0.58% (95% CI 0.42-0.75%) and 0.60% (95% CI 0.37-0.83%), respectively, p=0.83; (ii) autosome gain - 0.15% (95% CI 0.09-0.21%) and 0.22% (95% CI 0.14-0.30%), respectively, p=0.39; (iii) chromosome X gain - 1.11% (95% CI 0.90-1.31%) and 1.01% (95% CI 0.85-1.17%), respectively, p=0.30. The frequency of mosaic aneuploidy over the background level was found in 19 (16%) of 116 children with idiopathic autism, while outlier values were not found in controls (p=0.0019). Conclusions: Our findings identify low-level aneuploidy as a new genetic risk factor for autism. Therefore, molecular cytogenetic analysis of somatic mosaicism is warranted in children with unexplained autism.

Integrins are heterodimeric transmembrane glycoproteins that function as key adhesion and cell signalling receptors. A functional polymorphism in the integrin beta3 subunit encoded by the ITGB3 gene, Leu33Pro, has been shown to modify a variety of traits of beta3-expressing cells. To analyse the role of this functional polymorphism in modifying BRCA1-associated ovarian and breast cancer risks, a case-control study was performed among Polish BRCA1 mutation carriers including 319 breast cancer cases, 146 ovarian cancer cases and 290 controls unaffected by breast and ovarian cancer, in situ breast cancer or any other kind of cancer. Genotyping analysis was performed using PCR-based restriction fragment length polymorphism analysis. Odds ratios were calculated using univariate and multivariate logistic regression, taking into account a series of confounding variables, including the presence of related study subjects, that potentially could have biased any association. The results revealed that the ITGB3_Leu33Pro polymorphism was associated with a 2.5-fold increased risk of ovarian cancer, whereas no association with breast cancer risk was found. Thus, it appears that the ITGB3_Leu33Pro polymorphism may potentially increase the risk of ovarian cancer in Polish women with an inherited BRCA1 mutation.

International audience; BACKGROUND: Chromosomal rearrangements, arising from unequal recombination between repeated sequences, are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams-Beuren critical region (WBCR), located at 7q11.23, is commonly deleted in Williams-Beuren microdeletion syndrome (WBS). However, only four patients with a duplication of the WBCR have been reported to date: one with severe language delay and the three others with variable developmental, psychomotor and language delay. OBJECTIVE AND METHODS: In this study, we screened 206 patients with autism spectrum disorders for the WBCR duplication by quantitative microsatellite analysis and multiple ligation-dependent probe amplification. RESULTS: We identified one male patient with a de novo interstitial duplication of the entire WBCR of paternal origin. The patient had autistic disorder, severe language delay and mental retardation, with very mild dysmorphic features. CONCLUSION: We report the first patient with autistic disorder and a WBCR duplication. This observation indicates that the 7q11.23 duplication could be involved in complex clinical phenotypes, ranging from developmental or language delay to mental retardation and autism, and extends the phenotype initially reported. These findings also support the existence of one or several genes in 7q11.23 sensitive to gene dosage and involved in the development of language and social interaction.

A recent study, looking at the lifetime risk of developing malignant peripheral nerve sheath tumour (MPNST) in patients with neurofibromatosis type 1 (NF1), estimated the risk to be 8–13%. Prior to this, longitudinal studies had shown that patients with NF1 had a risk of 4–5% of developing MPNST, and cross‐sectional studies had found that only 1–2% of patients with NF1 had MPNST. The aim of this study was to estimate the lifetime risk of MPNST in patients with NF1 in southern Scotland, using patient records obtained from the Edinburgh and Glasgow Genetic Units and Scottish Cancer Register. In the period 1993–2002, 14 patients with NF1 were diagnosed with MPNST in a population of 3.5 million. The lifetime risk of MPNST in the Scottish patients with NF1 was calculated to be 5.9–10.3%. This provides further evidence that patients with NF1 are at greater risk of developing MPNST than was previously estimated, and emphasises the importance of educating patients about suspicious symptoms, which may need an urgent medical opinion. The mean age at diagnosis of MPNST (p

A novel missense mutation in the mediator of RNA polymerase II transcription subunit 12 (MED12) gene has been found in the original family with Lujan syndrome and in a second family (K9359) that was initially considered to have Opitz–Kaveggia (FG) syndrome. A different missense mutation in the MED12 gene has been reported previously in the original family with FG syndrome and in five other families with compatible clinical findings. Neither sequence alteration has been found in over 1400 control X chromosomes. Lujan (Lujan–Fryns) syndrome is characterised by tall stature with asthenic habitus, macrocephaly, a tall narrow face, maxillary hypoplasia, a high narrow palate with dental crowding, a small or receding chin, long hands with hyperextensible digits, hypernasal speech, hypotonia, mild‐to‐moderate mental retardation, behavioural aberrations and dysgenesis of the corpus callosum. Although Lujan syndrome has not been previously considered to be in the differential diagnosis of FG syndrome, there are some overlapping clinical manifestations. Specifically, these are dysgenesis of the corpus callosum, macrocephaly/relative macrocephaly, a tall forehead, hypotonia, mental retardation and behavioural disturbances. Thus, it seems that these two X‐linked mental retardation syndromes are allelic, with mutations in the MED12 gene.

Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is the autosomal dominant heritable syndrome with predisposition to development of renal cell carcinoma and smooth muscle tumours of the skin and uterus. Objective: To measure the fumarate hydratase (FH) enzyme activity in lymphoblastoid cell lines and fibroblast cell lines of individuals with HLRCC and other familial renal cancer syndromes. Methods: FH enzyme activity was determined in the whole cell, cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations. Results: Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with HLRCC had lower FH enzyme activity than cells from normal controls (p

Background: Idiopathic ( primary) hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in genes encoding sarcomeric proteins. One of the most commonly mutated HCM genes is the myosin binding protein C (MYBPC3) gene. Mutations in this gene lead mainly to truncation of the protein which gives rise to a relatively mild phenotype. Pure HCM in neonates is rare and most of the time childhood HCM occurs in association with another underlying condition.Objective: To study the presence of mutations in the MYBPC3 gene in idiopathic childhood HCM.Methods: MYBPC3 coding region and splice junction variation were analysed by denaturing high performance liquid chromatography (DHPLC) and sequencing in DNA isolated from two neonates with severe unexplained HCM, who died within the first weeks of life.Results: Truncating mutations were found in both alleles of the MYBPC3 gene in both patients, suggesting there was no functional copy of the MYBPC3 protein. Patient 1 carried the maternally inherited c. 2373_2374insG mutation and the paternally inherited splice-donor site mutation c.1624+1G -> A. Patient 2 carried the maternally inherited frameshift mutation c.3288delA (p.Glu1096fsX92) and the paternally inherited non-sense mutation c.2827C -> T (p.Arg943X).Conclusions: The findings indicate the need for mutation analysis of genes encoding sarcomeric proteins in childhood HCM and the possibility of compound heterozygosity.

We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan‐Herndon‐Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction. The c.1834delC segregates with the disease in this family and it was not present in 100 control chromosomes, further confirming its pathogenicity. This mutation causes a frameshift and the inclusion of 64 additional amino acids in the C‐terminal region of the protein. Pathogenic mutations in the MCT8 gene, which encodes a thyroid hormone transporter, results in elevated serum triiodothyronine (T3) levels, which were confirmed in four affected males of this family, while normal levels were found among obligate carriers. Through in vitro functional assays, we showed that this mutation decreases cellular T3 uptake and intracellular T3 metabolism. Therefore, the severe neurological defects present in the patients are due not only to deficiency of intracellular T3, but also to altered metabolism of T3 in central neurones. In addition, the severe muscle hypoplasia observed in most AHDS patients may be a consequence of high serum T3 levels.

Semaphorins are a large family of transmembrane proteins. The gene for SEMA4A encodes a transmembrane protein comprising 760 amino acids. To investigate its association with human retinal degeneration, mutation screening of the SEMA4A gene was carried out on 190 unrelated patients suffering from a variety of eye diseases. We report the first observation of the involvement of SEMA4A gene mutations causing retinitis pigmentosa (RP) and cone rod dystrophy (CRD). We screened the DNA of 135 patients with RP, 25 patients with CRD, and 30 with LCA using SSCP and direct DNA sequencing for mutations in the SEMA4A gene. Two mutations, p.D345H and p.F350C, were observed only in affected patients; they were not observed in any of the normal members or the 100 control subjects. Both mutations identified occur in the conserved semaphorin domain. Multiple sequence alignments using Clustal analysis showed that R713Q is a conserved substitution and D345H is a semi‐conserved substitution. We conclude that these mutations are a cause of various retinal degenerations.

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

We have established the Developmental Genome Anatomy Project (DGAP; //dgap.harvard.edu) to take advantage of the unique opportunity to locate genes of developmental importance provided by apparently balanced chromosomal rearrangements associated with phenotypic abnormalities. By positional cloning at or near the breakpoints, we aim to identify the crucial disease genes whose functions have been disrupted by rearrangement.1 Kallmann’s syndrome (KS) is a developmental disorder characterised by anosmia resulting from agenesis of the olfactory lobes and hypogonadism secondary to deficiency of hypothalamic gonadotropin releasing hormone (GnRH). Its prevalence has been estimated at 1/10 000 in males and 1/50 000 in females. In a minority of cases there are inactivating mutations of KAL1, an X linked gene encoding a putative adhesion molecule thought to mediate embryonic neuronal migration.2,3 Constitutional autosomal chromosome translocations associated with KS have been reported, but the disrupted genes have not been identified.4–6 We have studied a white male subject with a de novo balanced translocation between chromosomes 7, in band p12.3, and 8, in band p11.2 (fig 1A), who was diagnosed on clinical examination to have hypogonadotropic hypogonadism (infantile testes), azoospermia, and cleft lip and palate, without frank anosmia. As a KS patient with a microdeletion involving the same 8p11.2 region had been reported, we sought to identify the chromosome 8 gene disrupted in this reciprocal translocation as a likely candidate for the cause of autosomal KS as well as of isolated hypogonadotropic hypogonadism.7 While this breakpoint in FGFR1 was being characterised, Dode et al identified FGFR1 mutations in several patients, establishing that disruption of FGFR1 can cause autosomal dominant KS.8 Figure 1 Fluorescent in situ hybridisation (FISH) mapping of the chromosome 8 breakpoint. (A) Ideogram illustrating the balanced t(7;8)(p12.3;p11.2) in the patient. (B) FISH mapping with RP11-100B16, labelled with SpectrumOrange, resulted in hybridisation …

Characteristic deformities of skull shape occur as a result of different patterns of sutural fusion, while compen- satory skull expansion occurs at unaffected sutures to accommodate the growing brain. Premature fusion of the sagittal suture, for example, results in anterior to posterior elongation of the skull known as scaphocephaly. 2 Sagittal synostosis is the most common type of craniosynostosis, occurring in 40-58% of cases reported in large neurosurgical surveys, and shows a male predominance. 3-6 Most of the cases in these reports are ''non-syndromic'' instances of sagittal synostosis, while familial cases represent 2-9% of the total. Mental retardation is uncommon in isolated sagittal synostosis, but is more common in cases with associated malformations. 4-6

Hearing impairment is a common and highly heterogeneous sensory disorder. Genetic causes are thought to be responsible for more than 60% of the cases in developed countries.1 In the majority of cases, non-syndromic hearing impairment is inherited in an autosomal recessive pattern.2 Thirty eight different loci and 20 genes for autosomal recessive non-syndromic hearing impairment (ARNSHI) have been identified to date.3 In many populations, up to 50% of all cases of ARNSHI are caused by mutations in the DFNB1 locus (MIM 220290) on 13q12.4 This locus contains the GJB2 gene (MIM 121011), encoding connexin-26 (Cx26),5 which belongs to a family of transmembrane proteins with about 20 members in humans. Hexamers of connexins (connexons) are displayed in the plasma membrane. Docking of connexons on the surfaces of two adjacent cells results in the formation of intercellular gap junction channels.6 Several different connexins, including Cx26, have been shown to participate in the complex gap junction networks of the cochlea.7,8 It has been postulated that these networks play a key role in potassium homeostasis, which is essential for the sound transduction mechanism.9 Given the high prevalence of DFNB1 deafness, molecular testing for GJB2 mutations has become the standard of care for the diagnosis of patients with non-syndromic hearing impairment of unknown cause.10 However, the finding of a large number of affected subjects with only one GJB2 mutant allele complicates the molecular diagnosis of DFNB1 deafness. In different studies, these have accounted for 10–50% of deaf subjects with GJB2 mutations.4 It was hypothesised that there could be other mutations in the DFNB1 locus but outside the GJB2 gene. This hypothesis gained support by the finding of a deletion in the DFNB1 locus outside GJB2 but truncating the neighbouring GJB6 gene (MIM 604418), which …

Hodgkin’s disease was recently designated Hodgkin lymphoma (HL) in the World Health Organization Classification.1 The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) population based registries estimate that 7900 new cases are diagnosed annually in the USA.2 Clues to its aetiology have been suggested by the bimodal age distribution; higher risks in males, in people with higher socioeconomic status, and in smaller families; and occurrence of Epstein-Barr virus in HL tumour cells.3 The importance of genetic factors is indicated by reports of multiply affected families from case series,4–6 a twin study,7 a case–control study,8 and population registry studies carried out in Utah,9 Denmark,10 Israel,11 and Sweden.12–14 We recently analysed data from registries in Sweden and Denmark and found significant familial aggregation of HL and other lymphoproliferative tumours.15 The relative risk for HL among first degree relatives of cases compared with controls was 3.1. Relative risks were higher in males compared with females, and in siblings of cases compared with parents and offspring. Relatives of earlier onset cases were at higher risk for HL and for all lymphoproliferative tumours and were also at higher risk for developing early onset tumours themselves. These findings are consistent with those seen from earlier case series studies but have the advantage of being from large, population based samples. It is not known whether or how extrinsic risk factors interact with genetic susceptibility. Identifying inherited susceptibility genes is an important step towards defining the pathway(s) leading to development of HL and understanding its complex aetiology. There have been many studies of somatic mutations in HL tumour cells, but although there are associations with HLA types, specific germline genes causing susceptibility have not yet been identified. Early studies of HLA Class I alleles …

3-7 The extent of TNFa expression has been shown to be associated with the overall allele frequency and genotype distribution of the NcoI restriction fragment length polymorphism in the first intron of the TNFb locus. 89 In an in vitro endotoxin stimulation model, the extent of TNF expression has been correlated to the genotype of a single base polymorphism in the 2308 promoter region of the TNFa gene. 10 In contrast to this finding, the clinical importance of polymorphisms in the TNFa gene remains controversial. Survival in severe sepsis 11 has not been associated with genotype distribution of single base mutation in the 2308 promoter region of the TNFa gene. Focussing on neonatal morbidity, neither the development of chronic lung disease of prematurity 12 nor necrotising enterocolitis 13 were correlated to genotype distribution of the TNFa gene, whereas the development of intraventricular haemorrhage (IVH) was correlated to the 2308 promoter region polymorphism of the TNFa gene. 12 Genetic determina

Background: Placental mesenchymal dysplasia (PMD) is a distinct syndrome of unknown aetiology that is associated with significant fetal morbidity and mortality. Intrauterine growth restriction is common, yet, paradoxically, many of the associated fetuses/newborns have been diagnosed with Beckwith-Wiedemann syndrome (BWS). Methods: We report two cases of PMD with high levels of androgenetic (complete paternal uniparental isodisomy) cells in the placenta and document, in one case, a likely androgenetic contribution to the fetus as well. Results: The same haploid paternal complement found in the androgenetic cells was present in coexisting biparental cells, suggesting origin from a single fertilisation event. Conclusions: Preferential allocation of the normal cells into the trophoblast explains the absence of trophoblast overgrowth, a key feature of this syndrome. Interestingly, the distribution of androgenetic cells appears to differ from that reported for artificially created androgenetic mouse chimeras. Androgenetic mosaicism for the first time provides an aetiology for PMD, and may be a novel mechanism for BWS and unexplained intrauterine growth restriction.

Background: Espins are actin bundling proteins present in hair cell stereocilia. A recessive mutation in the espin gene ( Espn ) has been detected in the jerker mouse and causes deafness, vestibular dysfunction, and hair cell degeneration. More recently mutations in the human espin gene ( ESPN ) have been described in two families affected by autosomal recessive hearing loss and vestibular areflexia. Objective: To report the identification of four additional ESPN mutations (S719R, D744N, R774Q, and delK848) in patients affected by autosomal dominant hearing loss without vestibular involvement. Results: To determine whether the mutated ESPN alleles affected the biological activity of the corresponding espin proteins in vivo, their ability to target and elongate the parallel actin bundles of brush border microvilli was investigated in transfected LLC-PK1-CL4 epithelial cells. For three mutated alleles clear abnormalities in microvillar length or distribution were obtained. Conclusions: The results further strengthen the causative role of the espin gene in non-syndromic hearing loss and add new insights into espin structure and function.

Background: A higher frequency of skewed X chromosome inactivation has been reported in a consecutive series of young patients with breast cancer compared with controls of a similar age. Objective: To investigate the X inactivation pattern in patients with familial non- BRCA1 / BRCA2 breast cancer (n = 272), BRCA1 / BRCA2 germline mutations (n = 35), and sporadic breast cancer (n = 292). Methods: X inactivation pattern was determined by polymerase chain reaction analysis of the highly polymorphic CAG repeat in the androgen receptor ( AR ) gene. The X inactivation pattern was classified as skewed when 90% or more of the cells preferentially expressed one X chromosome. Results: Young patients with familial breast cancer had a significantly higher frequency of skewed X inactivation (11.2%) than young controls (2.7%) (p = 0.001). There was also a strong tendency for middle aged patients with sporadic breast cancer to be more skewed than middle aged controls (13.6% v 4.4%) (p = 0.02). No association between skewed X inactivation and breast cancer was found for the BRCA1 / BRCA2 patients . Conclusions: Skewed X inactivation may be a risk factor for the development of breast cancer in both sporadic and familial breast cancer and may indicate an effect of X linked genes.

Although amyloidogenic transthyretin (ATTR) mutations are common in several populations, such as black Americans, the small number of diagnosed patients homozygous for TTR amyloid and the short follow up in most studies has until now prevented an analysis of their phenotype. In Sweden, nine homozygous patients from eight families carrying the ATTR mutation Val30Met, which gives rise to fatal neuropathic amyloidosis (FAP), have been identified and have now been followed for up to 15 years. This has enabled an analysis of the phenotype of homozygous patients. Genetic testing and detection of amyloid deposits in the vitreous body or in intestinal or skin biopsies confirmed the diagnosis in all patients. The patients' symptoms were obtained from medical records. For comparison, we used a group of 35 heterozygous non-transplanted patients with FAP (18 men and 17 women), who had been evaluated at the Department of Medicine, Umeå University Hospital before their deaths. Vitreous amyloidosis was the most prevalent symptom in the homozygous group, and in two patients it was the only manifestation of the disease during their lifetime. The age at onset was not different from that of heterozygous patients, and their survival tended not to be shorter but actually longer than for heterozygotes. Homozygosity for the mutation associated with FAP, ATTR Val30Met, does not implicate a more severe phenotype for Swedish patients. The most common symptom was vitreous opacity, which may be the only manifestation of the disease. These findings point to the possibilities of different pathways for amyloid formation, or the presence of hitherto unknown genes operating in amyloid formation.

Enlargement of the vestibular aqueduct (EVA) and its contents, the endolymphatic sac and duct, is the most common radiologic malformation of the inner ear associated with sensorineural hearing loss.1 It may occur alone or in combination with an incomplete partition of the apical turn of the cochlea as part of a complex of malformations known as a Mondini deformity.2 Hearing loss in ears with EVA is typically pre- or perilingual in onset, sensorineural or mixed, and fluctuating or progressive. EVA may be unilateral or bilateral; asymmetry of the hearing loss and the anatomic defect is common in bilateral cases.3–5 EVA has been observed in Pendred syndrome (PS; MIM 274600),6 branchio-oto-renal syndrome (MIM 113650),7 CHARGE (MIM 214800),8 Waardenburg syndrome (MIM 193500, 193510, 600193, 606662),9 and distal renal tubular acidosis with deafness (MIM 267300).10 Familial non-syndromic hearing loss with EVA was described in 199611 and numerous subsequent reports (DFNB4 (MIM 600791), enlarged vestibular aqueduct syndrome (MIM 603545)). EVA is always detected when the ears of individuals with PS are evaluated by both computed tomography (CT) and magnetic resonance imaging (MRI),6 and it has been estimated that PS may comprise up to 10% of prelingual deafness worldwide.3,12,13 PS is inherited in an autosomal recessive manner and is comprised of bilateral hearing loss, EVA, and an iodine organification defect in the thyroid gland, which may lead to goitre. PS is clinically differentiated from non-syndromic EVA by the presence of the thyroid iodine organification defect because goitre is an incompletely penetrant feature of PS.3 When goitre does occur in PS, it is most often euthyroidal and not evident until the second decade of life.3,12,14,15 There can be intrafamilial variability of the goitre, and PS phenocopies with …

Keratoconus (KC; MIM 148300) is a non-inflammatory corneal thinning disorder. Progressive thinning and protrusion of the cornea lead to loss of visual acuity for which the only effective treatment is corneal transplantation. The estimated prevalence of KC is 1–4 per 2000 in the general population.1 The age of onset is often at puberty, and the disorder is progressive until the third or fourth decade of life when it usually arrests. KC is a major cause of corneal transplantation in developed countries. The cause of KC is still unknown. Histological observations have demonstrated degradation of the corneal epithelium basal membrane, diminution of the number of collagen fibrils, thinning of the corneal stroma, and keratocyte apoptosis.2,3 Biochemical studies describe increased activity of metalloproteinases (MMP-2 and MMP-9) and lower expression of protease inhibitors such as α1-protease inhibitor.4,5 Sporadic KC is the most common presentation; however, a positive familial history has been reported in at least 6–10% of patients.1 Twin studies performed since the advent of modern computerised videokeratoscopy have reported four monozygotic pairs concordant for KC and two monozygotic pairs which were discordant,6–9 suggesting a genetic component for KC. Keratoconus prevalence in first degree relatives of KC patients is significantly higher than in the general population, demonstrating familial aggregation of the trait.10,11 Most published studies have suggested autosomal dominant inheritance of KC with incomplete penetrance or variable expression.1,12 Autosomal recessive inheritance as well as rare cases of X linked inheritance have also been described.10,13 In some rare cases, KC is associated with other genetic disorders such as trisomy 21, atopy, and Leber congenital amaurosis.14,15 KC gene localisation efforts to date have been carried out in rare large families or in population isolates where genetic heterogeneity is minimised. …

Background: The aim of the study was to assess underlying genetic cause(s), clinical features, and response to therapy in catecholaminergic polymorphic ventricular tachycardia (CPVT) probands. Methods and results: We identified 13 missense mutations in the cardiac ryanodine receptor (RYR2) in 12 probands with CPVT. Twelve were new, of which two are de novo mutations. A further 11 patients were silent gene carriers, suggesting that some mutations are associated with low penetrance. A marked resting sinus bradycardia off drugs was observed in all carriers. On beta blocker treatment, 98% of the RYR2 mutation carriers remained symptom free with a median follow up of 2 (range: 2-37) years. Conclusion: CPVT patients with RYR2 mutation have bradycardia regardless of the site of the mutation, which could direct molecular diagnosis in (young) patients without structural heart disease presenting with syncopal events and a slow heart rate but with normal QTc at resting ECG. Treatment with b blockers has been very effective in our CPVT patients during initial or short term follow up. Given the risk of sudden death and the efficacy of b blocker therapy, the identification of large numbers of RYR2 mutations thus calls for genetic screening, early diagnosis, and subsequent preventive strategies

Contains fulltext : 48887.pdf (Publisher’s version ) (Closed access) Truncating mutations were found in the PHF8 gene (encoding the PHD finger protein 8) in two unrelated families with X linked mental retardation (XLMR) associated with cleft lip/palate (MIM 300263). Expression studies showed that this gene is ubiquitously transcribed, with strong expression of the mouse orthologue Phf8 in embryonic and adult brain structures. The coded PHF8 protein harbours two functional domains, a PHD finger and a JmjC (Jumonji-like C terminus) domain, implicating it in transcriptional regulation and chromatin remodelling. The association of XLMR and cleft lip/palate in these patients with mutations in PHF8 suggests an important function of PHF8 in midline formation and in the development of cognitive abilities, and links this gene to XLMR associated with cleft lip/palate. Further studies will explore the specific mechanisms whereby PHF8 alterations lead to mental retardation and midline defects.

Contains fulltext : 48352.pdf (Publisher’s version ) (Closed access) BACKGROUND: In BRCA2 mutation carriers, increased risks have been reported for several cancer sites besides breast and ovary. As most of the families included in earlier reports were selected on the basis of multiple breast/ovarian cancer cases, it is possible that risk estimates may differ in mutation carriers with a less striking family history. METHODS: In the Netherlands, 139 BRCA2 families with 66 different pathogenic mutations were included in a nationwide study. To avoid testing bias, we chose not to estimate risk in typed carriers, but rather in male and female family members with a 50% prior probability of being a carrier (n = 1811). The relative risk (RR) for each cancer site with the exception of breast and ovarian cancer was determined by comparing observed numbers with those expected, based on Dutch cancer incidence rates. RESULTS: We observed an excess risk for four cancer sites: pancreas (RR 5.9; 95% confidence interval (CI) 3.2 to 10.0), prostate (2.5; 1.6 to 3.8), bone (14.4; 2.9 to 42.1) and pharynx (7.3; 2.0 to 18.6). A small increase was observed for cancer of the digestive tract (1.5; 1.1 to 1.9). Histological verification was available for 46% of the tumours. Nearly all increased risks reached statistical significance for men only. Cancer risks tended to be higher for people before the age of 65 years. Moreover, families with mutations outside the previously defined ovarian cancer cluster region tended to have a higher cancer risk. CONCLUSIONS: We found that BRCA2 carriers are at increased risk for cancers of the prostate and pancreas, and possibly bone and pharynx. Larger databases with extended follow up are needed to provide insight into mutation specific risks of selected carriers in BRCA2 families.

he cerebellar ataxias are a heterogeneous group of neurodegenerative disorders, characterised by symptoms and signs of cerebellar degeneration, pyramidal and extrapyramidal features, and variable polyneuropathy. Prominent clinical features are signs of cerebellar ataxia, such as uncoordinated gait and uncontrolled co-ordination of hand, speech, and eye movements, while (extra) pyramidal signs, such as retinal, cardiac, muscle and/or neuronal involvement, are less common. The clinical picture shows a large variation in age at onset and disease progression. Sporadic ataxias may be attributed to various toxic, inflammatory, paraneoplastic, metabolic, endocrinal, or malabsorption conditions. Hereditary ataxias consist of a large number of autosomal dominant ataxias and ataxias with an autosomal recessive and X-linked mode of inheritance. The remaining ataxias of unknown cause are referred to as idiopathic sporadic cerebellar ataxias. Most symptomatic ataxias can be diagnosed on the basis of a typical history or by simple laboratory tests. In hereditary ataxias family history is important. However, a negative family history cannot rule out autosomal recessive or X-linked ataxia and even autosomal dominantly inherited ataxia may be missed because of reduced penetrance, the early death of gene carriers before the onset of symptoms, imprinting effects, variable expression, adoption, or nonpaternity. 1

The recent barrage of linkage assignments and gene discoveries has confirmed the clinical and genetic heterogeneity of ataxic diseases. They all share the prototypic feature of difficulty in walking though many additionally present dysarthria, spasticity, retinopathy, and other neurological symptoms.1 Broad subgroups of ataxias and related diseases exist including spinocerebellar and spastic ataxias, each with their own characteristic features. The clinical and genetic heterogeneity of ataxias is best represented by the autosomal dominant cerebellar ataxias (ADCAs). Indeed, a minimum of 22 loci have been discovered, including those for the spinocerebellar ataxias (SCA1–8, SCA10–17, SCA19, SCA21, and SCA22),2–8 the episodic ataxias EA19 and EA2,10 and the complex disorder, dentatorubropallidoluysian atrophy (DRPLA).11 Similarly, Friedreich’s ataxia (FRDA) is an autosomal recessive disease which affects the spinocerebellar and pyramidal tracts. Symptoms are typically noticed before 20 years of age and include dysarthria, nystagmus, areflexia, and a positive Babinski sign.12 Hereditary spastic ataxia (HSA) is characterised by retinopathy, muscle wasting, nystagmus, and dysarthria.13 Spastic ataxia (SAX1) is the first described dominant form,14 while the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is one of a number of recessive forms.15 All told, the loci responsible for a significant proportion of hereditary causes of ataxias still have not been elucidated.16 A large amount of heterogeneity is also observed within the hereditary neuropathies. These include the hereditary sensory neuropathies (HSNs)17 and the more common hereditary motor and sensory neuropathies (HMSNs).18 Sensory ataxia is not present in the HSNs,19 since they affect mainly the unmyelinated and small myelinated nerve fibres, nor is it present in the HMSNs, where sensory symptoms are seldom the presenting complaint. A few rare families have been described with a hereditary sensory-motor neuropathy associated with ataxia (SMNA) of neuropathic origin.20– …

eigh syndrome is a subacute necrotising encephalomyelopathy characterised by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs. The main laboratory findings are raised lactate in the blood and cerebrospinal fluid, but the diagnosis is only confirmed by the presence of bilateral symmetrical lesions in the basal ganglia, thalamus, brain stem, and cerebellum. Leigh syndrome can result from a number of different defects in mitochondrial energy metabolism, most commonly deficiencies of cytochrome oxidase (COX), pyruvate dehydrogenase, NADH-ubiquinone oxidoreductase (Complex I) and ATP synthase. 1 In patients with Leigh syndrome and cytochrome oxidase deficiency, the underlying genetic defect is usually a mutation in the SURF1 gene, which maps to chromosome 9q34 and encodes a cytochrome oxidase assembly factor. 23 In a small number of cases, Leigh syndrome and cytochrome oxidase deficiency have been found in patients with mutations in mitochondrial DNA (mtDNA) 45 and in one patient with mutations in the COX10 gene. 6

The discovery of fetal DNA in the plasma of pregnant women1 has led to the development of promising approaches for non-invasive prenatal diagnosis.2–6 However, as fetal and maternal DNA species co-exist in maternal plasma, these DNA based diagnostic applications depend largely on the use of genetic markers that would allow the discrimination between fetal and maternal DNA (for example, the Y chromosome of a male fetus), and thus, a particular genetic marker could generally only be used in a proportion of pregnancies. This situation has prompted a quest by many laboratories to develop fetal nucleic acid markers that are independent of sex or polymorphism. The detection of fetal RNA in maternal plasma7 offers new possibilities for non-invasive prenatal investigation. This field has recently taken on new momentum as robust methods for plasma RNA extraction have been developed8 and circulating RNA has been shown to be surprisingly stable,9 possibly through an association with particulate matter.8 Furthermore, recent studies have identified the placenta as a significant source of such circulating fetal RNA.10 Hence, placental expressed mRNA transcripts, such as those coding for human placental lactogen ( hPL ), human chorionic gonadotropin β subunit ( βhCG ),10 and corticotropin releasing hormone ( CRH ),11 have been shown to be detectable in maternal plasma. Quantitative assays have been developed for the measurement of these circulating mRNA transcripts.8 The pregnancy specificity of these mRNA species has been demonstrated by their rapid clearance from maternal plasma after delivery.10,11 Thus, the detection in maternal plasma of mRNA transcripts derived from the plasma offers new avenues for the development of fetal specific nucleic acid markers that are independent of sex and polymorphism for the non-invasive prenatal assessment of all pregnancies.12 The clinical value of such an approach has …

Familial hypertrophic cardiomyopathy (FHC) is typically characterised by left ventricular hypertrophy, diastolic dysfunction, and hypercontractility, and is often associated with disabling symptoms, arrhythmias, and sudden death.1 FHC shows both non-allelic and allelic genetic heterogeneity, and results from any one of more than 100 mutations in genes encoding sarcomeric proteins.2 Identified genes include those encoding β myosin heavy chain, the myosin regulatory and essential light chains, myosin binding protein C, troponin I, troponin C, α cardiac actin, and titin.2,3 The FHC phenotype is characterised by hypertrophy, myocyte disarray and fibrosis, and results from the dominant negative expression of one of these (mainly missense) mutations. The resulting sarcomeric dysfunction leads ultimately, through mechanisms that remain obscure, to pathological left ventricular remodelling. However, as molecular defects are identified in only half the cases, it is likely that non-sarcomeric genes may also be responsible. Non-sarcomeric causes of FHC are largely uncharacterised, and may be associated with distinct or compound phenotypes. Similarly, hereditary sensorineural hearing loss shows a great degree of non-allelic and allelic genetic heterogeneity, and can be dominant, recessive, X linked, or mitochondrial.4–6 Hereditary sensorineural hearing loss is classified according to mode of inheritance and the presence of clinically detectable extra-auditory manifestations (syndromic deafness) or their absence (non-syndromic).6,7 The distributions of mutant gene expression are not necessarily restricted to clinically affected organ systems, and mutant genes associated with “non-syndromic” deafness may therefore have subtle extra-auditory manifestations. Genetic syndromes restricted to a cardio-auditory phenotype include the long QT syndrome (LQTS) caused by mutations in KvLQT1 ( KCNQ1 ) or in KCNE1 , where QT prolongation has autosomal dominant expression (Romano Ward syndrome), but congenital sensorineural hearing loss with LQTS is autosomal recessive (Jervell and Lange-Nielsen syndrome).8 In the LQTS, cardiac structure is normal. Recently, Schonberger et al …

HGPS recapitulates most of the pathologies of normal aging at an accelerated rate, with sparing of the nervous system. 3 Children with HGPS usually appear normal in early infancy, but at about six months of age begin to experience profound growth delay. 4 Scalp hair, eyebrows, and eyelashes are typically lost resulting in total alopecia. 5 A gradual, almost complete lipodystrophy begins in infancy, and the skin acquires an abnormally aged appear- ance with prominent veins. In some children osteolysis may affect the clavicles, terminal phalanges, and acetabulum, and sometimes even more severe bone deformities occur, 6

Gene dose alterations can cause mental retardation (MR), congenital malformations and miscarriages. Standard chromosome analysis by G-banding has a limited resolution, but molecular cytogenetic techniques, such as multi-subtelomeric FISH, microdeletion FISH, multicolour FISH and comparative genomic hybridisation (CGH), have played an important role for the diagnosis of MR during the past decade.1 A complete set of subtelomeric FISH probes was presented in 1996 and updated in 2000.2 Consequently, screening for subtelomeric abnormalities has become a diagnostic test that is offered by diagnostic laboratories, and a number of studies reporting new subtelomeric rearrangements have been published.3–16 However, these probes only reveal chromosome rearrangements located in the subtelomeric region. To cover the whole genome, genome wide screening for chromosomal imbalances using microsatellite markers has been reported,17,18 as well as metaphase CGH.19–22 Yet none of these techniques is able to offer a high resolution screening of the whole genome for chromosome imbalances. The development of accurate and sensitive genome wide screening methods would facilitate the clinical diagnosis of patients with very small or subtle rearrangements. Screening for chromosomal imbalances by array CGH, whether using cDNA23 or BAC clones,24 has mainly been performed on cancer samples,25–30 which usually contain large gene dose alterations. Although array CGH has provided a higher resolution compared to conventional CGH, it has not yet become a widely applied method for the analysis of gene dose alterations in individuals with idiopathic mental retardation. It has been a challenge to achieve the adequate performance needed for the reliable detection of single copy losses or gains of very small regions. Chromosome specific micro-arrays have however been used in a few cases to determine the critical regions in microdeletion disorders.31,32 In this report we used a cDNA micro-array and …

Terminal deletions of the long arm of chromosome 2 (2q37) have been recorded in the literature for more than a decade and an associated syndrome first became apparent when nine patients were reported with an Albright hereditary osteodystrophy (AHO)-like metacarpal/metatarsal shortening (brachymetaphalangism).1,2 This is also known as brachydactyly-mental retardation syndrome (BDMR, MIM 600430). To date, some 60 or so cases of 2q37 deletion or monosomy resulting from unbalanced translocations have been reported. Significant variability in clinical presentation is apparent, but almost all patients have some degree of mental retardation and facial dysmorphism. Brachymetaphalangism has been reported in approximately 50% of cases.1–15 Congenital heart anomalies are present in around 20% of patients with 2q37 monosomy,16–22 compared to 1% of the general population. These are predominantly atrial or ventricular septal defects, but more complex problems have been reported.17,22 Additionally, there are two reports of tetralogy of Fallot with monosomy 2q37 resulting from unbalanced translocations,23,24 but both cases were also trisomic for 17q25 and it is not clear which imbalance was causative. Other phenotypes repeatedly associated with 2q37 deletions include Wilms tumor and urogenital anomalies,6,17,19 epilepsy,1,2,7–9,14,16,20,25–27 eczema,2,5–7,16,28,29 and autism or repetitive, hyperkinetic behaviour.1,2,5,7,10,11,15,16,19,25,26,28–32 Situs abnormalities have been reported in two cases9 and holoprosencephaly in one infant.33 Most 2q37 rearrangements reported to date have been only minimally characterised by conventional cytogenetics or subtelomeric fluorescent in situ hybridisation (FISH). A small number have been subjected to more detailed analysis using multiple FISH clones or microsatellite markers,2,10,15,26 but the ability to assign breakpoints and make genotype–phenotype correlations has been …

Multiple epiphyseal dysplasia (MED) is clinically and genetically a heterogeneous disorder that affects growth centres and results in delayed and irregular mineralisation of the ossification centres.1,2 Recessively inherited MED (rMED; MIM 226900) accounts for a significant proportion of MED cases and is associated with mutations in the sulphate transporter gene, DTDST/SLC26A2.3,4 More often, MED is inherited as a dominant trait. Thus far, five different genes have been implicated in dominantly inherited MED: the gene for cartilage oligomeric matrix protein, COMP (MIM 600310); the genes for the α1, α2, and α3 chains of collagen IX, COL9A1 (MIM 120165), COL9A2 (MIM 120260), and COL9A3 (MIM 120270); and the gene for matrilin-3, MATN3 (MIM 602109). Patients with the severe forms of MED have short stature and major disability because of joint pain and stiffness. In the milder forms, height can be normal and joint complaints minimal. Mutations in COMP typically lead to the severe forms of dominant MED (MIM 132400) and can also cause a related but more severe disorder—pseudoachondroplasia (PSACH, MIM 177170). COMP is a pentameric extracellular glycoprotein that belongs to the thrombospondin protein family.5–7 It consists of a coiled coil N-terminal domain responsible for pentamerisation, four epidermal growth factor (EGF)-like repeats, eight thrombospondin type 3 (T3) repeats, and a large C-terminal globular domain. Mutations in COMP that cause MED are located in the T3 repeats.1,2 Mutations in these repeats alter the conformation of the protein and affect its ability to bind calcium.8–10 No mutations have been reported in the N-terminal domain or the EGF-like domains in MED. Only four mutations causing MED have been found in the C-terminal domain—two (T585R and T585M) in patients with unclassified MED,1,11 and the other two (R718W and N742fsX743) in patients with “severe MED” …

Obesity, defined as a body mass index (BMI) of greater than 30 kg/m2, has become a worldwide public health problem.1 About 250 million adults, roughly 7% of the world adult population, are considered obese and two or three times as many may be overweight with BMI of 25–30 kg/m2.2 A recent analysis shows that the health care cost of obesity is probably between 0.89% and 4.32% of the national expenditure in the United States.3 Obesity is associated with many diseases such as type 2 diabetes mellitus, hypertension, coronary heart disease, and certain forms of cancer.1 As a complex disease, obesity is determined by multiple genetic and environmental factors, including physiological, behavioural, and sociocultural factors.4–7 Numerous molecular genetics studies have been launched to search for the genes underlying the variations of obesity phenotypes, resulting in a host of candidate genes and potentially important genomic regions.8 Apolipoprotein E (APOE), coding a glycoprotein that plays a central role in lipid metabolism, is considered as a prominent candidate gene for obesity. APOE binds with high affinity to the low density lipoprotein (LDL) receptor and facilitates endocytosis of the associated lipoprotein particle.9 In addition, APOE mediates lipoprotein interactions with the LDL receptor related protein, very low-density lipoprotein receptor, and other lipoprotein receptors.9,10 Some studies have reported positive associations between APOE genotypes and some obesity phenotypes,11–14 whereas negative results were observed for the other obesity phenotypes.13–15 The transforming growth factor beta 1 (TGF-β1) gene codes a multifunctional cytokine that controls proliferation, differentiation, and other functions in many cell types, including adipocyte precursor cells.16 Increased TGF-β1 expression was associated with BMI and abdominal adipose tissue in morbid obesity.17 A recent study suggested an association between TGF-β1 polymorphism …

Telangiectases are characterised by an abnormal permanent dilatation of end vessels—mainly venules but occasionally also capillaries and arterioles—in the subpapillary plexus in the upper part of the dermis.1 Hereditary benign telangiectasia (HBT; OMIM 187260) is a rare genetic skin disorder classified among the primary or idiopathic telangiectases.1 Affected individuals present with widespread cutaneous plaque-like, punctate, radiating or arborising telangiectases, which usually appear in early childhood with a random distribution. The young lesions are small and red and tend to increase in size with age, becoming softer and salmon-pink, almost like normal skin.2,3 Lesions are invariably asymptomatic but can be responsible for mild cosmetic disability. There is no bleeding diathesis or systemic vascular lesions. Thus HBT is considered the benign form of hereditary haemorrhagic telangiectasia (HHT or Rendu-Osler-Weber disease; OMIM 187300 and 600736).4 Several familial cases showing autosomal dominant inheritance have been described.2–3,5–10 However, owing to the small size of these families, no locus has been identified so far. Capillary malformation (CM or “port wine stain”; OMIM 163000) is a common vascular anomaly occurring in 0.3% of newborns and can be inherited as an autosomal dominant trait with incomplete penetrance and variable expression.11–13 CM usually presents as a single flat lesion located in the head and neck, typically changing in colour from pink to purple with age.11 In published reports, HBT and CM have often been considered distinct disorders, based on the clinical presentation of cutaneous lesions, but overlapping phenotypes have been described in some families.8,12 A locus for CM has recently been mapped to a 23-cM region on chromosome 5q13–q15 ( CMC1 ).12,13 Here we report clinical and histological features of a large HBT family which showed linkage to CMC1 . ### Key points

Hypophosphatasia is an inherited disorder characterised by defective bone and tooth mineralisation and deficiency of serum and bone alkaline phosphatase activity. The bone symptoms are highly variable in their clinical expression and range from stillbirths without mineralised bone to pathological fractures developing only late in adulthood.1 Odontohypophosphatasia is characterised by premature exfoliation of fully rooted primary teeth and/or severe dental caries, often not associated with abnormalities of the skeletal system.2,3 The anterior deciduous teeth are more likely to be affected and the most frequently lost are the incisors.4 Dental x rays show reduced alveolar bone and enlarged pulp chambers and root canals.2,4 Although the only clinical feature is dental disease, biochemical findings are generally indistinguishable from those in patients with mild forms of hypophosphatasia (adult and childhood). While perinatal hypophosphatasia and infantile hypophosphatasia are transmitted as an autosomal recessive trait, both autosomal recessive and autosomal dominant transmission may be found in childhood, adult, and odontohypophosphatasia.3,5–9 The distinction between recessive and dominant transmission may be difficult to determine conclusively by using familial analysis because expression of the disease is very variable, with parents of even severely affected children showing no or extremely mild symptoms of the disease.9,10 The tissue non-specific alkaline phosphatase (TNSALP) is a phosphomonoesterase anchored at its carboxyl terminus to the plasma membrane by a phosphatidylinositol-glycan moiety.11 The enzyme cleaves extracellular substrates pyridoxal-5′-phosphate (PLP), phosphoethanolamine (PEA), and inorganic pyrophosphates (PPi). Its exact function in bone and dental mineralisation is still unclear but probably involves hydrolysis of Ppi12 and perhaps mammalian specific activities such as collagen and calcium binding.13 The TNSALP gene is localised on chromosome 1p36.114 and consists of 12 exons distributed over 50 kb.15 More than 127 distinct mutations have been described …

Branchio-oto-renal syndrome (BOR, OMIM 113650) is an autosomal dominant disorder characterised by the association of hearing loss (HL), structural ear anomalies, branchial arch defects, and renal anomalies.1 The prevalence approximates 1:40 000 in the general population, and has been reported in about 2% of deaf children.2 Age of onset for deafness varies from childhood to early adulthood.3 The clinical expression of BOR exhibits wide intra- and interfamilial variability. In addition, reduced penetrance for BOR has been assumed.4 The major feature of BOR, which occurs in 93% of patients, is HL, which can be conductive, sensorineural, or mixed. Besides the classical ear, kidney, and branchial arch anomalies, different developmental manifestations of BOR in other organ systems have been described. Among these, dysfunction of the lacrimal duct system is a common association.5–10 Thus, BOR represents a clinically and genetically heterogeneous disease complex that manifests predominantly during organogenesis. A gene locus for autosomal dominant BOR had been localised on chromosome 8q13.11,12 Subsequently, mutations in the human homologue of the Drosophila eyes absent gene (EYA1) have been shown to be causative for BOR (OMIM 601653).13 Branchio-otic syndrome (BOS) (OMIM 602588) was initially described as a disorder distinct from BOR, featuring the same clinical symptoms as BOR with the exception of renal anomalies.1 The large variety of clinical phenotypes and the description of mutations in the EYA1 gene for BOR and BOS patients13–15 show that BOR and BOS can represent allelic defects of the EYA1 gene. The identification of a second gene locus in a large BOS pedigree on chromosome 1q31 established the presence of genetic locus heterogeneity for BOS.4 No linkage to this locus has been published for BOR families and the gene defect is still to be identified. The issue …

Obstructive pulmonary disease is an important health problem in all populations, and bronchiectasis of unknown aetiology (idiopathic bronchiectasis, IB) contributes significantly to the disease. The gene responsible for cystic fibrosis (CF), the cystic fibrosis transmembrane regulator ( CFTR ), was shown to have a role in the manifestation of IB, as gene mutations and a significantly high proportion of allele T5 of the polythymidine tract (Tn) in intron 8 (IVS8) have been observed in patients.1–5 However, the complex genetic basis of the phenotype expression of IB remains largely unknown. CFTR mutations alone cannot be held responsible for the disease, as obligate CFTR mutation heterozygotes were shown not to have an increased risk for IB.6 The CFTR gene seems to act in a multifactorial context, as both the mutations and polymorphic alleles exert their effects in an incompletely penetrant fashion. Therefore, environmental factors and/or other genes are believed to contribute to the disease. IB is only one of the several single organ diseases to which the CFTR gene contributes. Some other such diseases are asthma,7 obstructive azoospermia,8–11 allergic bronchopulmonary aspergillosis,12 and idiopathic chronic pancreatitis.13,14 ### Key points

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder associated with a variety of benign and malignant lesions such as cafe au lait spots, neurofibromas, phaeochromocytomas, pilocytic astrocytomas, and malignant peripheral nerve sheath tumours.1–3 With an incidence of 1 in 4000, NF1 is caused by genetic alterations of the NF1 gene located on 17q11.2.4–6 Consisting of 60 exons, the NF1 gene is a tumour suppressor gene which leads to tumorigenesis upon inactivation of both alleles.7–9 Spinal tumours cause neurological symptoms in about 2% of NF1 patients and can be detected in 40% of NF1 patients by magnetic resonance imaging (MRI).10 Patients with multiple spinal tumours but very few or no other clinical symptoms of NF1, including three multigenerational families,11–13 have been reported, suggesting a subgroup or a distinct genetic form of NF1, spinal neurofibromatosis (SNF).14 In one of these multigenerational families, a truncating mutation in exon 46 of the NF1 gene was found.13 However, no systematic study of the clinical spectrum of patients with spinal tumours and of the NF1 mutations associated with it has been carried out. In this study, we performed a clinical and molecular examination of patients from 17 families with spinal tumours. Neurofibromatosis type 1 (NF1) was diagnosed based on the NIH criteria.15 The protocol was approved by the institutional review board and all participants provided informed consent. The 17 index patients and 11 family members were examined in our NF clinic in Hamburg. Detailed MRI results of the full spine were available from the 17 patients and three affected family members.10 DNA was extracted from blood using a QIAamp Blood Kit from Qiagen (Hilden, Germany). Mutation analysis was performed by direct sequencing of all NF1 exons using a BigDye Sequencing kit as previously …

Autism is a developmental disorder characterised by a triad of clearly abnormal or impaired development in social interaction and communication, and a markedly restricted repertoire of activity and interests.1 Its incidence is estimated at about 1/1000 to 1/2000.2 Different metabolic and structural brain anomalies have been observed in subjects with autism but these data have not yet led to a single unifying theory on its pathogenesis. In a minority (5–10%) of cases, autism is a symptom of a recognisable disorder such as fragile X syndrome, tuberous sclerosis, or untreated phenylketonuria.3 However, the molecular pathways involved in these disorders have also not contributed to an increased understanding of the pathogenesis of autism. In the majority of cases, the cause of autism is not known but there is strong evidence for a genetic cause. A polygenic inheritance is likely but estimates on the number of interacting genes vary from two to 10.4,5 Moreover, it is likely that different combinations of genes are implicated in unrelated subjects.6 The identification of genes involved in autism is expected to increase our understanding of the pathogenesis of this disorder. Several large scale linkage studies and follow up analyses have yielded suggestive linkage to several different chromosomal regions. However, neither this approach nor the large number of association studies using candidate genes has resulted in the identification of autism susceptibility genes.5 As an alternative approach to identifying candidate genes for autism, we initiated a positional cloning strategy starting with subjects with autism carrying a de novo chromosomal anomaly. In a group of 525 subjects with autism who were karyotyped and had no recognised underlying medical condition, four were found to carry such a de novo chromosomal aberration. In none of them was there a family history of autism. Three had …

Hemihypertrophy, or hemihyperplasia, is a condition in which there may be asymmetrical overgrowth of the cranium, face, trunk, and/or limbs on one side of the body.1 There may also be asymmetrical visceromegaly on the ipsilateral or contralateral side.2 Hemihypertrophy may occur in isolation, hence the term “isolated hemihypertrophy (IH)”, or as part of a number of overgrowth syndromes in which other characteristic clinical features are present. Such syndromes include neurofibromatosis, Klippel-Trenaunay-Weber syndrome, McCune-Albright syndrome, and Beckwith-Wiedemann syndrome (BWS).1 The incidence of IH is ∼1/86 000 live births,3 with a male:female ratio of 1:2.1 The aetiology of IH is unknown. A number of different chromosomal anomalies, including diploid-triploid mosaicism and trisomy 18 mosaicism, have been identified, and the causes of IH are likely to be heterogeneous.2 It has been suggested that IH may be one end of the spectrum of phenotypes of BWS, linked to the chromosomal locus 11p15.1 Here we report a case of apparently isolated hemihypertrophy in one of a pair of monozygotic twins, with paternal uniparental disomy in an area of the 11p15 locus associated with BWS. The subjects of the study are a pair of female twins, one of whom (twin 2) has hemihypertrophy. Twin 1 has a normal physical appearance. The twins were born at 36 weeks of gestation by normal vaginal delivery. Twin 1 weighed 2730 g and twin 2 weighed 3205 g. Apgar score at birth was 10 for each girl. Twin 1 fed well and gained weight as expected with no neonatal problems. Twin 2 initially failed to pass meconium and was intolerant of feeds. She was noted to have hemihypertrophy affecting the right leg and arm and an ultrasound scan showed enlargement of the right kidney. She was given a glycerine suppository and passed meconium …

Hereditary non-polyposis colorectal cancer (HNPCC) syndrome is a dominantly inherited condition, recognised by Lynch et al 1 in 1966, associated with a major susceptibility to colorectal and endometrial cancer. The use of stringent criteria in the definition of the syndrome led to the initial identification of two genes, MSH2 and MLH1 , which when mutated are responsible for the cancer susceptibility. Mutations in these two genes may account for up to two-thirds of all HNPCC cases.2 More recently, additional genes such as MSH6 , PMS1 , PMS2 , MLH3 , TGFβRII , and EXO1 have also been implicated. Together deleterious mutations of these genes account for less than 10% of the cases. In addition to the colorectum and endometrium, a variety of different sites have been reported to be at an increased risk of cancer in HNPCC patients. Indeed, studies based on either family history or on small groups of patients with identified mutations suggested that carcinomas of the ureter, stomach, small bowel, ovary, and biliary tract1,3 were more frequently encountered than in the general population. In addition to this tumour spectrum, the presence of sebaceous skin tumours and keratoacanthomas or of glioblastomas defines two different subsets within the HNPCC syndrome, called Muir-Torre4 or Turcot5 syndromes, respectively. Finally, more recently, an excess of breast cancer has also been reported but remains controversial.6 Following these descriptions, several management and follow up programmes for HNPCC families have been proposed.7,8 To delineate these procedures more precisely, it would be useful to gain further insight into the associated risks of MSH2 and MLH1 mutations. Prospective recruitment of 436 consecutive patients referred to a French family cancer clinic enabled the identification of 348 subjects from 163 families with an established deleterious mutation in either MSH2 or MLH1 …

The neurofibromatoses are a group of neurocutaneous disorders that show extreme clinical heterogeneity and are characterised by growth abnormalities in tissues derived from the embryonic neural crest.1,2 Two main clinical forms exist, type 1 (NF1) and type 2 (NF2), as well as several alternate and related forms.2,3 NF1 and NF2 are the only clinically well defined disorders and both genes have been identified.4–8 The NIH diagnostic criteria for NF1, as defined by the conference statement,9 are met if two or more of the following are found: six or more CAL spots; two or more neurofibromas of any type or one plexiform neurofibroma; axillary or inguinal freckling; optic glioma; two or more Lisch nodules; a distinct osseous lesion; a first degree relative (parent, sib, or offspring) with NF1 according to the above criteria. Spinal nerve sheath tumours are described as symptomatic findings in only 5% of NF1 patients,10 although they can be observed by MRI in up to 36% of patients.11–13 The presence of a wide, symmetrical distribution of spinal neurofibromas, occurring in all adult affected members of the same family and segregating in an autosomal dominant fashion, is however extremely rare. This form, familial spinal NF (FSNF), has been considered an alternate form of NF since patients generally lack dermal neurofibromas and Lisch nodules, both typical hallmarks of NF1, and since symptomatic and generalised spinal neurofibromas are uncommon in classical NF1. FSNF has been reported in only four families.12,14,15 Three multigenerational families with spinal neurofibromas and CAL spots were shown to be linked to markers surrounding the NF1 locus.12,14,15 In the fourth family, presenting with spinal neurofibromas without CAL spots, linkage to the NF1 locus was excluded.14 Only in one FSNF family has …