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Introduction XYdisorders of sex development (DSD) result from variants in many different human genes but frequently have no detectable molecular cause. In approximately 25% of cases of XY DSD, the index case may have associated malformations. Genetic disorders of endoplasmic reticulum (ER) function are increasingly being recognised but have not been associated with DSD or pituitary disorders. Clinical case Three siblings (with unaffected non-consanguineous parents) were reviewed at the tertiary endocrine clinic. Child I was noted at birth to have cliteromegaly. Imaging and examination under anaesthetic revealed a normal vagina and uterus but gonads of indeterminate origin. She was 46,XY and basal endocrine investigations at the age of 4 years showed a low AMH for male but otherwise normal gonadal and thyroid function and normal IGF-1. She had a laparoscopic bilateral gonadectomy aged 5 years. Pathology demonstrated bilateral testicular tissue, with substantial fibrotic atrophic change and occasional placental alkaline phosphatase (PLAP) positive cells, suggestive of germ cell tumours. Aged 8 years she developed obesity and later hypertension. Child II was reviewed due to short stature and diagnosed with GH deficiency aged 2 years. She has normal adrenal and thyroid function and gonadotrophins. MRI demonstrated an ectopic posterior pituitary. Child III presented with perineal hypospadias, a small phallus, bilateral undescended testes and craniofacial abnormalities. Endocrine investigations revealed hypogonadotrophic hypogonadism, with no testosterone response to hCG stimulation, a low normal AMH and no response of LH or FSH on LHRH stimulation. He has panhypopituitarism with an ectopic posterior pituitary gland on MRI and is currently on treatment with GH, hydrocortisone and levothyroxine. His BP is on the 98th centile for age and height. Child I and Child III have mild developmental delay but are in mainstream school with additional educational support. High-throughput DNA sequencing revealed, in all three siblings, a heterozygous truncating variant in the SEC31A gene that encodes a component of the COPII-complex that coats the vesicles mediating ER to Golgi transport. CRISPR-Cas9 targeted knockout of the corresponding Sec31a region resulted in embryonic lethality in homozygous mice. mRNA phenotyping of ER-related genes demonstrated increased mRNA expression of ATF4 and CHOP in the affected children, genes encoding key ER stress-related proteins, associated with defective protein transport. Conclusions Dysregulation ofanterograde and retrograde COPII-coated-vesicle ER-Golgi transport is increasingly recognised to underlie human developmental disorders, including Craniolenticulosutural dysplasia (OMIM 607812) and Saul-Wilson syndrome (OMIM 618150). The de novo SEC31A nonsense variant in all three affected siblings, the ER stress response, plus reported developmental syndromes with dysfunction of this transport mechanism and evidence from the preclinical mouse model suggest that SEC31A might underlie a previously unrecognised clinical syndrome comprising DSD, endocrine abnormalities, dysmorphic features and developmental delay. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Ther objective of our study was to use an established cohort of boys to investigate common patterns of malformations in those with hypospadias. We performed a retrospective review of the phenotype of participants in the Deciphering Developmental Disorders Study with neurodevelopmental delay and an 'Abnormality of the genital system'. This group was divided into two subgroups: those with hypospadias and without hypospadias. Associated phenotypes of the two subgroups were compared and analysed. Of the 166 Deciphering Developmental Disorders participants with hypospadias and neurodevelopmental delay, 47 (28%) had cardiovascular and 40 (24%) had structural brain abnormalities. The rate of cardiovascular abnormalities in those with neurodevelopmental delay and genital abnormalities other than hypospadias (N = 645) was lower at 19% (P = 0.001). In addition, structural brain malformations were higher at 24% in the hypospadias group versus 15% in the group without hypospadias (P = 0.002). The constellation of these features occured at a higher rate in the hypospadias group versus the no hypospadias group (P = 0.038). In summary, this is the first study to indicate that cardiovascular and brain abnormalities are frequently encountered in association with hypospadias in children with neurodevelopmental disorders. Not only do these associations provide insight into the underlying aetiology but also they highlight the multisystem involvement in conditions with hypospadias.

PURPOSE: Widespread, quality genomics education for health professionals is required to create a competent genomic workforce. A lack of standards for reporting genomics education and evaluation limits the evidence base for replication and comparison. We therefore undertook a consensus process to develop a recommended minimum set of information to support consistent reporting of design, development, delivery, and evaluation of genomics education interventions.METHODS: Draft standards were derived from literature (25 items from 21 publications). Thirty-six international experts were purposively recruited for three rounds of a modified Delphi process to reach consensus on relevance, clarity, comprehensiveness, utility, and design.RESULTS: The final standards include 18 items relating to development and delivery of genomics education interventions, 12 relating to evaluation, and 1 on stakeholder engagement.CONCLUSION: These Reporting Item Standards for Education and its Evaluation in Genomics (RISE2 Genomics) are intended to be widely applicable across settings and health professions. Their use by those involved in reporting genomics education interventions and evaluation, as well as adoption by journals and policy makers as the expected standard, will support greater transparency, consistency, and comprehensiveness of reporting. Consequently, the genomics education evidence base will be more robust, enabling high-quality education and evaluation across diverse settings.

There is a well-recognized growing need for improved access to online genetic and genomics education for professionals, students, teachers, and the public. Numerous individual online genetic and genomic educational resources have been developed, but many are difficult to identify or locate when required. Consequently, an easily navigated website, European Society of Human Genetics (ESHG) Genetic Educational Materials and Sources (https://www.EuroGEMS.org), has recently been created, on behalf of the ESHG, by the authors. It facilitates access by a wide variety of target audience types and levels to a broad range of 110 selected, free, high-quality educational online genetic and genomic resources around the world, including several in languages other than English. The website has been endorsed by the ESHG, directly linked from that society's web pages, and has now been used in over 105 countries.

Background: \ud A good response to levodopa is a key feature of Parkinson's disease (PD), and a poor response suggests an alternative diagnosis, but the extent of variation in the levodopa response in definite PD is not well defined.\ud \ud Literature Review: \ud A systematic review of articles reporting pathologically confirmed PD and levodopa responsiveness from 1971 to 2018 was performed using the medical subheadings “postmortem,” “Parkinson's disease,” "levodopa," and “l ‐dopa” in PubMed, Embase, and Latin American and Caribbean Health Sciences Literature (LILACS) databases.\ud \ud Cases: \ud A total of 12 articles described 445 PD cases: 61.7% male, age at disease onset 64.0 years (SD 9.6), age at death 77.1 years (SD 7.2). Levodopa responsiveness was reported in 399 cases (89.7%) either as a graded or a binary response. In the 280 cases (70.2%) describing a graded response, it was excellent in 37.5%, good in 45.7%, moderate in 12.1%, and poor in 4.6%. In the 119 cases describing a binary response (29.8%), 73.1% were levodopa responsive, and 26.9% were nonresponsive. Comorbid brain pathology was present in 137 of 235 cases assessed, being cerebrovascular in 46.0% and Alzheimer's disease in 37.2% of these, but its contribution to levodopa responsiveness was unclear.\ud \ud Conclusions: \ud The levodopa motor response varies in definite PD. Explanations other than diagnostic inaccuracy should be explored.

Purpose: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. Methods: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. Results: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. Conclusion: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants., SCOPUS: ar.j, info:eu-repo/semantics/published

A range of phenotypes that are associated with disorders of sex development (DSD) may also be encountered in patients with neurodevelopmental delay. In this study we have undertaken a collaborative retrospective review of anonymised phenotypic and genotypic data from the UK-wide Deciphering Developmental Disorders (DDD) study. Our objectives were to determine the frequency and range of DSD phenotypes observed in participants in the DDD study and to identify novel genetic associations. We found that of 7,439 DDD participants, 603 (8%) had at least one genital abnormality. In addition, we found that DSD occurs in 5% of patients with learning difficulties. Causative mutations were found in 13 developmental genes, of which, crucially, 6 had no previous reported association with DSD. Our findings indicate that recognition of these associations should not be overlooked in the management of patients with complex conditions and that exomic sequencing through projects like DDD increases diagnostic yield.

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n=64), others having SEMD (n=5), Kniest dysplasia (n=7), spondyloperipheral dysplasia (n=2), or Torrance-like dysplasia (n=2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders. (c) 2015 Wiley Periodicals, Inc.

This is the final published version. It was originally published by Portland Press in Clinical Science here: http://www.clinsci.org/cs/126/cs1260721.htm.

Pheochromocytoma/paraganglioma occurs almost exclusively after paternal transmission of succinate dehydrogenase D (SDHD) mutations. This parent-of-origin effect has not been fully explained but is accompanied by obligate loss of the maternal copy of chromosome 11. Loss of wild-type SDHD and an additional imprinted gene (hypothesized to be H19) appears necessary for tumor formation. Two previous reports suggested tumor formation after maternal transmission of SDHD mutation, but histological and molecular characterization was unavailable.We report the first kindred in which histologically confirmed pheochromocytoma/paraganglioma occurred after maternal transmission of an SDHD mutation and investigate the molecular mechanism of tumor formation.The design of the investigation was the study of a three-generation family with SDHD c.242CT (p.Pro81Leu) mutation.The index patient had a histologically confirmed pheochromocytoma and an identical SDHD germline mutation (p.Pro81Leu) to her mother (who had a glomus jugulare tumor) and paraganglioma tissue from her maternal grandfather. Tumor DNA from the index patient revealed loss of heterozygosity (LOH) at 11q23, causing loss of the wild-type paternal SDHD allele and LOH affecting maternal 11p15, including H19. These two regions of LOH were separated by a region exhibiting clearly retained heterozygosity, including SDHAF2, a recently reported paraganglioma susceptibility gene.Tumor formation can occur after maternal transmission of SDHD, a finding with important clinical implications for SDHD families. Tumor formation in SDHD mutation requires the loss of both the wild-type SDHD allele and maternal 11p15, leading to the predominant but now not exclusive pattern of disease inheritance after paternal SDHD transmission.

Summary Background Cutaneous melanoma is rapidly increasing in incidence worldwide and approximately 5% of melanomas are hereditary. Deletions in chromosome 1p36 have been detected in melanoma but no candidate melanoma tumour suppressor gene has yet been found in this area. Recently, strong evidence has been reported that CHD5 is a tumour suppressor gene in this region. Objectives To investigate CHD5 involvement in familial melanoma. Methods Peripheral blood DNA from 47 melanoma families who do not carry mutations in any of the three currently recognized melanoma genes, 398 patients with sporadic melanoma and 398 geographically matched nonmelanoma-bearing controls were studied. Linkage investigation, single nucleotide polymorphism (SNP) genotyping and mutation screening studies were carried out on the CHD5 locus. Results The CHD5 gene was not excluded by linkage analysis in any of the families. On SNP genotyping, the CHD5 rs7513548 SNP was found to be significantly associated with sporadic melanoma (odds ratio 1·53, 95% confidence interval 1·13–2·06). The AG genotype was found in 208 cases and 169 controls (cf. 141 and 175 cases and controls, respectively, for the AA genotype). On CHD5 mutation screening, a total of 50 single-base substitutions were detected. Of these, 39 were intronic and 11 were exonic. While 32 were previously recognized variants, 18 were newly identified. Three, in exons 4, 31 and 32, led to nonsynonymous substitutions. A p.Met1576Ile substitution was identified in a mother and daughter, both with invasive cutaneous melanoma. Conclusions This study appears to be the first report of CHD5 variants in familial cutaneous melanoma. Such CHD5 variants could block or alter the ability of CHD5 to regulate the cell cycle pathway and to effect cellular control. As only one of the 47 families studied has this variant, it appears to be a rare event and further screening of melanoma families is required to confirm whether or not CHD5 is involved in melanoma pathogenesis.

In this chapter, the general principles regarding the genetic causes of childhood tumors are discussed. In addition, the main features of the more common genetic syndromes associated with childhood tumors are described, together with an outline of the underlying molecular mechanisms. Point mutations and also larger, chromosomal, changes are described. Practical advice is given for genetic counseling in general and more specific advice is provided for many of the syndromes. Details of helpful online sources of the latest information regarding cancer-related syndromes are given. Furthermore, to facilitate rapid access to such information, a freely accessible website is provided by the author, at www.essentialmedgen.com, that acts as a guide and portal to 70 international online resources, categorized according to content. Each internet resource contains detailed, up-to-date information regarding clinical details, testing laboratories, genes, proteins, analysis tools or patient support groups. Such information will provide a useful supplement to that contained herein.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominantly inherited conditions. A range of complications has been described, including gastrointestinal manifestations. Gastric carcinoid tumours are associated with multiple endocrine neoplasia, atrophic gastritis and pernicious anaemia but have not been reported in NF1 in the absence of other predisposing factors. We report the occurrence and investigation of a gastric carcinoid tumour in a 23-year-old woman with previously uncomplicated NF1. Analysis of the tumour tissue revealed loss of heterozygosity at the NF1 gene locus but a normal karyotype and an absence of microsatellite instability. A germline NF1 gene nonsense mutation in exon 37 was detected by denaturing high-performance liquid chromatography and DNA sequence analysis. This is the first reported occurrence of a gastric carcinoid tumour in a patient with NF1 in the absence of other predisposing factors such as pernicious anaemia. The analyses indicate that the carcinoid arose through NF1 gene inactivation but in the absence of an inherited NF1 gene microdeletion. This case adds to the range of gastrointestinal tumours that may be encountered in patients with NF1, particularly in those who present with upper gastrointestinal haemorrhage.

Advances in sequencing technologies are having a major impact on our understanding of the genetic causes of many human congenital disorders. Next generation sequencing (NGS) approaches are particularly important for determining the inherited genetic changes leading to disorders of sex development (DSD). Knowledge of the genetic pathways involved in ovary or testis development is incomplete and, currently, a molecular diagnosis is made in a minority of DSD cases. Here, we review the different NGS strategies applied to the analysis of rare diseases and highlight the potential pitfalls and advantages that are associated with each approach. We also discuss the problems of variant calling as well as the challenges involved in the identification and interpretation of pathogenic mutations from NGS datasets. As clinics start to use NGS on a routine basis, a close collaboration between the molecular and clinical geneticists is essential. This is particularly relevant in the context of unsolicited genetic findings, where clear guidelines regarding counseling, truly informed consent and precise data interpretation will be invaluable.

This second edition has been comprehensively updated to reflect current clinical practice and the latest technical developments, including pre-implantation genetic diagnosis, array CGH, QF-PCR, non-invasive prenatal diagnosis and next generation sequencing amongst others. The first section covers basic principles, while the second outlines the more common situations where obstetrics and gynaecology interact with medical genetics. The third section contains real-life clinical case scenarios which have been selected to represent typical problems and to highlight areas which, if mismanaged, could have serious medico-legal consequences. Together with its accompanying website (www.essentialmedgen.com), it provides an invaluable guide to the use and selection of useful online genetic resources. This book is essential reading for candidates preparing for the MRCOG postgraduate examination, and any health professionals requiring a clear understanding of medical genetics and its increasingly frequent uses in obstetrics and gynaecology, where incorrect genetic advice can have serious consequences.

Editor—The genetic counselling of a pregnant woman who carries an Xp chromosomal deletion is far from straightforward. While the precise locations of the CDPX1 (arylsulphatase E), steroid sulphatase ( STS ), and Kallman ( KAL1 ) genes are known and FISH probes are available for these well characterised genes, the positions of putative mental retardation genes in this region have not yet been determined. Clinical and molecular studies undertaken over the past 10 years on patients with distal Xp deletions imply, however, that the putative X linked mental retardation (XLMR) gene, MRX49 , lies distal to GS1 and STS but proximal to DXS31 and CDPX1 (fig1).1-4 Figure 1 (a) Case 6, (b) case 8, (c) case 9, (d) case 4, (e) case 12, and (f) case 13 of Ballabio et al,1 (g)-(j) cases BA16, BA20, BA139, and BA75 of Schaefer et al,3 (k) boy with IQ of 46, short stature, generalised ichthyosis, hypogonadotrophic hypogonadism, nystagmus, and photophobia,2 (l) boy with aggressive and hyperactive behaviour, myoclonic epilepsy, developmental delay, and no speech aged 4 years 8 months,4 (m) monozygous male twins with X linked ichthyosis, learning difficulties (LD), and epilepsy,10 (n) our patient, with short stature, Binder syndrome, and ichthyosis (consistent with the loss of the SHOX, CDPX1, and STS genes, respectively) but no significant learning difficulties. The presence (+) or absence (-) of LD is indicated for each case. A broken line indicates the chromosomal region within …

Many studies suggest that a multi-tissue tumour suppressor gene is located at human chromosome 7q31.1. We have cloned and characterized a novel gene at this locus. The TES gene lies within the minimal region of overlap of several LOH studies and appears to possess the properties of a tumour suppressor. TES is widely expressed and is predicted to encode a protein of 421 amino acids, with three C-terminal LIM domains. Mutation analysis of the coding TES exons in 21 human tumour-derived cell lines revealed the presence of a frameshift mutation in one allele in the breast cancer cell line ZR-75. Methylation of the CpG island at the 5' end of TES appears to be a remarkably frequent finding, occurring in seven out of 10 ovarian carcinomas and in each of the 30 tumour-derived cell lines tested. Moreover, forced expression of TES in HeLa or OVCAR5 cells, resulted in a profound reduction in growth potential, as determined by the colony formation assay. We believe that TES is a tumour suppressor gene that is inactivated primarily by transcriptional silencing resulting from CpG island methylation.

An 18 week male fetus is described with Acro-renal-mandibular syndrome. This third reported case of the syndrome is the first known male case and extends the phenotypic spectrum that characterizes the condition.

Advances in sequencing technologies are having a major impact on our understanding of the genetic causes of many human congenital disorders. Next generation sequencing (NGS) approaches are particularly important for determining the inherited genetic changes leading to disorders of sex development (DSD). Knowledge of the genetic pathways involved in ovary or testis development is incomplete and, currently, a molecular diagnosis is made in a minority of DSD cases. Here, we review the different NGS strategies applied to the analysis of rare diseases and highlight the potential pitfalls and advantages that are associated with each approach. We also discuss the problems of variant calling as well as the challenges involved in the identification and interpretation of pathogenic mutations from NGS datasets. As clinics start to use NGS on a routine basis, a close collaboration between the molecular and clinical geneticists is essential. This is particularly relevant in the context of unsolicited genetic findings, where clear guidelines regarding counseling, truly informed consent and precise data interpretation will be invaluable.

The genome’s structure is highly complex, in relation not only to its sequence but also to its spatial organization and compaction in chromatin around nucleosomal proteins. The degree of chromatin condensation is dynamic, regulated by multiple mechanisms that include covalent histone modifications and nucleosome repositioning. Gene expression, which is inversely related to chromatin compaction, is equally complex, involving regulation by proteins and by increasingly recognized small RNAs such as microRNAs. Gene expression is also affected by single-nucleotide polymorphisms and DNA copy number variants. The combined effects of these factors on gene expression include altered gene transcription, splicing patterns, and translation. The possible biological significance of the extensive regions of noncoding DNA in the genome is currently being investigated. Such data are essential to the interpretation of increasingly available whole genome array and sequencing results, both in research and in the clinical context.

Objective To clinically and genetically investigate women with mullerian disorders, including Mayer-Rokitanksy-Kuster-Hauser (MRKH) syndrome. Design Two-year prospective clinical and laboratory study. Setting Not applicable. Patient(s) Thirty-five women over 16 years of age with a mullerian disorder, including MRKH. Intervention(s) Women were recruited from specialist gynecology clinics or identified from the Scottish Disorders of Sex Development Register (www.sdsd.scot.nhs.uk/index.html). Associated abnormalities were detected by clinical examination, imaging studies, and biochemical analyses. Chromosomal microduplications and microdeletions were detected by array comparative genomic hybridization (CGH) and validated by fluorescence in situ hydridization. Main Outcome Measure(s) Identification of associated congenital and biochemical abnormalities and identification of regions of genomic imbalance using array CGH. Result(s) Associated congenital anomalies were common, present in 25/35 (71%) of affected women, particularly renal and skeletal abnormalities, which were present in 15/35 (43%) and 17/35 (49%) women, respectively. Using array CGH, novel or recurrent regions of genomic imbalance were identified in 4/11 (36%) women with MRKH and in 5/24 (21%) women with other mullerian abnormalities. Conclusion(s) Additional congenital abnormalities and regions of genomic imbalance are common in women with mullerian disorders, including MRKH. Recurrent microdeletions and microduplications associated with MRKH implicate specific possibly causative genes. The investigation of women with mullerian disorders should be thorough, and array CGH should be considered, given the potential highly significant familial implications of a chromosomal abnormality.

Cancer is a genetic disease, arising from the progressive accumulation of mutations that promote the clonal selection of cells with increasingly deregulated growth. Studies from many different fields, including tumor virology, chemical carcinogenesis, molecular biology, somatic cell genetics, and genetic epidemiology, have all provided fundamental insights into the genetic basis of cancer. Most of these alterations are somatically acquired, but some are inherited. During the last four decades, many of the genetic targets of the mutations have been identified. The cancer phenotype, however, is a result of complex interactions, involving not only the known cancer gene products but also a multitude of other proteins.

Background Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, β 4 ( PLCB4 ) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 ( GNAI3 ) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. Results We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. Conclusions These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.

From data collected via a large international collaborative study, we have constructed a growth chart for patients with molecularly confirmed congenital spondylo-epiphyseal dysplasia (SEDC) and other COL2A1 related dysplasias. The growth chart is based on longitudinal height measurements of 79 patients with glycine substitutions in the triple-helical domain of COL2A1. In addition, measurements of 27 patients with other molecular defects, such as arginine to cysteine substitutions, splice mutations, and mutations in the C-terminal propeptide have been plotted on the chart. Height of the patients progressively deviate from that of normal children: compared to normal WHO charts, the mean length/height is -2.6 SD at birth, -4.2 SD at 5 years, and -5.8 SD in adulthood. The mean adult height (male and female combined) of patients with glycine substitutions in the triple-helical region is 138.2cm but there is a large variation. Patients with glycine to cysteine substitutions tend to cluster within the upper part of the chart, while patients with glycine to serine or valine substitutions are situated between +1 SD and -1 SD. Patients with carboxy-terminal glycine substitutions tend to be shorter than patients with amino-terminal substitutions, while patients with splice mutations are relatively tall. However, there are exceptions and specific mutations can have a strong or a relatively mild negative effect on growth. The observation of significant difference in adult height between affected members of the same family indicates that height remains a multifactorial trait even in the presence of a mutation with a strong dominant effect. © 2012 Wiley Periodicals, Inc. Molecular Sequence Numbers: GENBANK: NM_001844; Chemicals/CAS: arginine, 1119-34-2, 15595-35-4, 7004-12-8, 74-79-3; asparagine, 70-47-3, 7006-34-0; cysteine, 4371-52-2, 52-89-1, 52-90-4; glycine, 56-40-6, 6000-43-7, 6000-44-8; valine, 7004-03-7, 72-18-4

Determining the precise cause of adrenal insufficiency occurring in infancy is of critical importance for both the correct management of affected children and the provision of correct genetic advice to their families. We report a case of a 24-year-old, male patient bearing a new mutation in the DAX1 gene. The patient was born at term, from a healthy pregnancy. Adrenal insufficiency was diagnosed in the fourth week of life with a salt-wasting syndrome, but it was mistakenly believed to be secondary to congenital adrenal hyperplasia (CAH). On hydrocortisone substitution, the child continued to develop normally, but the diagnosis of CAH was questioned, which led to an episode of an abrupt withdrawal of hydrocortisone substitution and subsequently caused a reoccurrence of a life-threatening salt-wasting syndrome. Owing to close follow-up, the patient's gonadal axis deficiency was promptly identified, which allowed an assisted but successful onset of puberty. We proposed the diagnosis of adrenal hypoplasia congenita (AHC) in this patient and identified a hemizygous mutation (c.1130delAinsGT, p.E377GfsX12) in exon 1 of the NR0B1 gene. To our knowledge, the detected mutation has not been described previously (HGMD Professional 2010.4, Human Gene Mutation Database, Biobase, Beverly, MA, USA). It leads to a frameshift, a premature stop codon, and, most likely, non-sense-mediated decay of the mutant mRNA. In this case, close patient follow-up minimized the detrimental consequences of an incorrect diagnosis. Nevertheless, it highlights the importance of the early precise diagnosis of patients with AHC.

The clinical details, specialist investigation, pharmacological treatment and outcome in 1000 consecutive patients referred to the epilepsy clinic at the Western Infirmary in Glasgow were reviewed. Data were collected by detailed proforma at initial referral and from the clinical notes at audit. 524 (52%) of the patients were 30 years of age or younger. 527 (53%) were sent to the clinic by their general practitioner with the majority of the remainder being referred by another hospital consultant. 240 (24%) came from outwith greater Glasgow. In 253 (25%) patients a possible predisposing factor was identified, usually a major head injury or alcohol abuse. Sixty (6%) patients suffered from additional mental handicap. Focal spike and wave activity was identified in 26% of electroencephalograms. One or more abnormality was found in 33% of the 356 patients who underwent computerized tomographic brain scanning. In 13 (11%) of these, a tumour was demonstrated. On referral, 65% of patients were being treated with antiepileptic drugs; 58% were on monotherapy and 42% took more than one anticonvulsant. The figure at audit was 77% treated, with a higher proportion (68%) than at referral receiving monotherapy (P < 0.005). Sedative anticonvulsants, such as phenobarbitone and primidone, were withdrawn in 29% of cases. 50% of the 519 patients, for whom seizure frequency data were available for the years before referral and audit, were seizure-free and seizure numbers had been reduced by 50% or more in a further 23%. A poorer response to treatment was associated with mental handicap (P < 0.05), birth injury (P < 0.01), and partial or secondary generalized seizures (P < 0.005).

Background Venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism, are common in older age. It has been suggested that statins might reduce the risk of VTE however positive results from studies of middle aged subjects may not be generalisable to elderly people. We aimed to determine the effect of pravastatin on incident VTE in older people; we also studied the impact of clinical and plasma risk variables. Methods This study was an analysis of incident VTE using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomized, double-blind, placebo-controlled trial of pravastatin in men and women aged 70-82. Mean follow-up was 3.2 years. Risk for VTE was examined in non-warfarin treated pravastatin (n = 2834) and placebo (n = 2865) patients using a Cox's proportional hazard model, and the impact of other risk factors assessed in a multivariate forward stepwise regression analysis. Baseline clinical characteristics, blood biochemistry and hematology variables, plasma levels of lipids and lipoproteins, and plasma markers of inflammation and adiposity were compared. Plasma markers of thrombosis and hemostasis were assessed in a nested case (n = 48) control (n = 93) study where the cohort was those participants, not on warfarin, for whom data were available. Results There were 28 definite cases (1.0%) of incident VTE in the pravastatin group recipients and 20 cases (0.70%) in placebo recipients. Pravastatin did not reduce VTE in PROSPER compared to placebo [unadjusted hazard ratio (95% confidence interval) 1.42 (0.80, 2.52) p = 0.23]. Higher body mass index (BMI) [1.09 (1.02, 1.15) p = 0.0075], country [Scotland vs Netherlands 4.26 (1.00, 18.21) p = 0.050 and Ireland vs Netherlands 6.16 (1.46, 26.00) p = 0.013], lower systolic blood pressure [1.35 (1.03, 1.75) p = 0.027] and lower baseline Mini Mental State Examination (MMSE) score [1.19 (1.01, 1.41) p = 0.034] were associated with an increased risk of VTE, however only BMI, country and systolic blood pressure remained significant on multivariate analysis. In a nested case control study of definite VTE, plasma Factor VIII levels were associated with VTE [1.52 (1.01, 2.28), p = 0.044]. However no other measure of thrombosis and haemostasis was associated with increased risk of VTE. Conclusions Pravastatin does not prevent VTE in elderly people at risk of vascular disease. Blood markers of haemostasis and inflammation are not strongly predictive of VTE in older age however BMI, country and lower systolic blood pressure are independently associated with VTE risk. Trial Registration Not applicable when study undertaken.

MMNP; International audience; Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

PUBLISHED, Background Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. Methods We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. Results We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10?7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. Conclusions We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype., Supported in part by grants from the National Institutes of Health (NIH) (HD043569, to Dr. Eichler), the South Carolina Department of Disabilities and Special Needs (to Drs. Skinner, Stevenson, and Schwartz), the Wellcome Trust (061183, to Dr. Tassabehji), the Andre & Cyprien Foundation and the University Hospitals of Geneva (to Drs. Antonarakis, Bena, and Gallati), and the European Union (EU) (project 219250, to Dr. Sharp; AnEUploidy project 037627, to Drs. Leeuw, Armengol, Antonarakis, Estivill, Veltman, and de Vries). The Irish Autism Study was funded by the Wellcome Trust and the Health Research Board (a grant to Drs. Gallagher and Gill). Dr. Poot was supported by a grant from the Dutch Foundation for Brain Research (Hersenstichting grant 2008(1) 34); Drs. Regan and Knight, by the Oxford Partnership Comprehensive Biomedical Research Centre; Dr. Willatt, by the Cambridge Biomedical Research Centre, with funding from the United Kingdom Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme; Drs. Huang and Maloney, as part of the National Genetics Reference Laboratory (Wessex) by the United Kingdom Department of Health; Ms. Buysse, as a research assistant of the Research Foundation?Flanders (FWO?Vlaanderen); and Dr. Eichler, as an investigator of the Howard Hughes Medical Institute.

Germline mutations in the tumor suppressor gene CDKN2A have been shown to predispose to cutaneous malignant melanoma. The M531 mutation is the most common CDKN2A mutation identified in Scottish melanoma patients and is also found in a small number of families in other countries. The aim of this study was to determine whether the occurrence of this mutation is due to a common ancestor originating from Scotland, and if so, to estimate how long ago the mutation arose. We examined 18 families carrying the M531 mutation: six from Scotland, five from Canada, four from Australia, and three from America. Haplotypes derived from segregation of seven informative microsatellite markers flanking CDKN2A were constructed in each family. Our findings show that 14 of 18 families carry a common ancestral haplotype on which the mutation arose similar to 88 generations ago (I-LOD-unit support interval 44-198 generations). This haplotype is very rare in controls, which supports the idea that it is a common founder mutation haplotype. The four M531 families that do not share the consensus haplotype may in fact have arisen from the same founder, but this is potentially obscured by presumed replication slippage for some of the microsatellite markers tested. (c) 2006 Wiley-Liss, Inc.

Skeletal dysplasias induced by mutations in the collagen 2 gene (the so-called "type 2 collagenopathies") form a wide spectrum in severity and are distinguished by subtle clinical and radiographic differential signs. The unifying features are predominant involvement of the vertebral bodies and the epiphyses of the long bones ("spondylo-epiphyseal" pattern). A mild degree of metaphyseal dysplasia can be seen in the so-called Strudwick variant of spondyloepimetaphyseal dysplasia and is generally mild or absent in other forms. We report here on four individuals with COL2A1 mutations associated with marked metaphyseal involvement with only mild epiphyseal and spondylar changes. One patient who carried a Gly283Arg substitution had a pattern of metaphyseal dysplasia that corresponded precisely to what was termed "Murdoch type metaphyseal dysplasia" in 1960s and was renamed Strudwick type SEMD in 1980s; the second patient carried a Gly181Arg substitution and had severe metaphyseal dysplasia with fractures at the metaphyses reminiscent of the "corner fractures" or Sutcliffe type spondylometaphyseal dysplasia. The third patient also had major metaphyseal involvement but more epiphyseal changes than the others in this study and had a Gly922Arg mutation in COL2A1. The final patient had a small in-frame deletion and unusually ballooned and distorted metaphyses. While it remains true that most individuals with COL2A1 mutations have chondrodysplasia with a spondylo-epiphyseal pattern, metaphyseal involvement is not incompatible with a COL2A1 dysplasia and mutation analysis can be indicated. The observation of these individuals with metaphyseal dysplasia indicates that the phenotypic spectrum associated with mutations in type 2 collagen, the main cartilage protein, is even wider than hitherto assumed.

We analyzed the insulin receptor gene in four patients with leprechaunism and one with type A insulin resistance. We detected novel and previously reported mutations. The novel mutants were expressed in Chinese hamster ovary cells to evaluate the consequences for insulin receptor function. A type A insulin resistance patient from Morocco was homozygous for Arg252His mutation, similar to a previously described type A patient from Japan. A patient with leprechaunism was homozygous for the Ser323Leu mutation, previously identified in homozygous form in two patients with Rabson-Mendenhall syndrome. Phenotypic expression of this mutation is variable. A patient with leprechaunism is compound heterozygous for the previously described Arg1092Trp mutation and a nonsense mutation in codon 897. Another patient with leprechaunism was homozygous for a novel Asn431Asp mutation, which only partially reduces insulin proreceptor processing and activation of signaling cascades. The novel Leu93Gln mutation that fully disrupts proreceptor processing was found in one allele in a patient with leprechaunism. A nonsense mutation at codon 1122 was in the other allele. These results expand the number of pathogenic insulin receptor mutations and demonstrate the variability in their phenotypic expression. The biochemical analysis of mutant insulin receptors does not reliably predict whether the phenotype will be leprechaunism, the Rabson-Mendenhall syndrome, or type A insulin resistance. The previously reported correlation between fibroblast insulin binding and duration of patient survival was not observed.

We report cataplexy, sudden atonic episodes provoked by emotion, in three patients with Prader–Willi syndrome (PWS) and suggest that cataplexy may be relatively common in this condition. Detailed questioning of the mother of an 18 year old woman who had PWS elicited a history of recurrent attacks, apparently induced by laughter, with sudden loss of power in all the patient's limbs. If …

The gene ST7 has been proposed as the multi-tissue tumor-suppressor gene (TSG) at chromosome 7q31.1. However, we have sought and failed to detect the truncating mutations reported to exist in this gene.

Over a 7 year period, 551 patients were investigated for the presence of a chromosome 22q11 deletion by fluorescence in situ hybridisation. Analysis of the presenting features of the 67 individuals with this chromosome deletion permitted us to devise guidelines to facilitate early diagnosis.