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DystrophicThus, the EB panel sequencing of genomic DNA, followed by a paternity test and analysis of microsatellite markers, as well as multiplex ligation-dependent probe amplification (MLPA) copy number analysis using patient and parental DNA, were performed.This approach revealed a paternally derived hemizygous deletion spanning from exon 3 to exon 118. Linear amplification-mediated PCR (LAM-PCR) determined the breaking points within intron 2 of the COL7A1 gene, comprising a 40kb segment within intron 1 of the adjacentThis report highlights the relevance of advanced molecular profiling to determine new/exceptional/unusual genotypes and the accurate mode of genetic transmission in DEB.

International audience; Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.

The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1, including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.

Contains fulltext : 169736.pdf (Publisher’s version ) (Closed access) Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-beta-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

Ring chromosome 20 syndrome is a rare chromosomal disorder characterized by childhood-onset drug-resistant epilepsy, behavioral problems and variable cognitive impairment. While most cases occur sporadically, parent-to-child transmission of ring 20 mosaicism has only been reported in a few exceptional families. We identified a further family with mother-to-child transmission of ring 20 mosaicism. Detailed characterization of the ring chromosome showed a complete ring with preserved telomere repetitive sequences. SNP genotyping excluded mosaic uniparental disomy and indicated that the chromosome was transmitted without recombination from mother to child. These results corroborate the findings of a previous study and support the hypothesis that inherited mosaicism is due to transmission of an unstable chromosome either prone to ring opening or to ring re-formation.

Context: Autosomal dominant hypophosphatemic rickets (ADHR) is the only hereditary disorder of renal phosphate wasting in which patients may regain the ability to conserve phosphate. Low iron status plays a role in the pathophysiology of ADHR. Objective: This study reports of a girl with ADHR, iron deficiency, and a paternal history of hypophosphatemic rickets that resolved without treatment. The girl's biochemical phenotype resolved with iron supplementation. Subjects: A 26-month-old girl presented with typical features of hypophosphatemic rickets, short stature (79 cm; −2.82 SDS), and iron deficiency. Treatment with elemental phosphorus and calcitriol improved her biochemical profile and resolved the rickets. The girl's father had presented with rickets at age 11 months but never received medication. His final height was reduced (154.3 cm; −3.51 SDS), he had undergone corrective leg surgery and had an adult normal phosphate, fibroblast growth factor 23, and iron status. Father and daughter were found to have a heterozygous mutation in exon 3 of the FGF23 gene (c.536G>A, p.Arg179Gln), confirming ADHR. Intervention: Withdrawal of rickets medication was attempted off and on iron supplementation. Results: Withdrawal of rickets medication in the girl was unsuccessful in the presence of low-normal serum iron levels at age 5.6 years but was later successful in the presence of high-normal serum iron levels following high-dose iron supplementation. Conclusions: We report an association between iron supplementation and a complete loss of biochemical ADHR phenotype, allowing withdrawal of rickets medication. Experience from this case suggests that reduction and withdrawal of rickets medication should be attempted only after iron status has been optimized.

Epilepsy is a common finding in patients with chromosomal macro- and micro-rearrangements but only few aberrations show a constant pattern of seizures. DNA array-based studies have reported causative copy number variations (CNVs) in 5-30% of patients with epilepsy with or without co-morbidities. The interpretation of many of the detected CNVs remains challenging. In order to identify CNVs carrying epilepsy-related genes we investigated 43 children with various patterns of epileptic seizures, intellectual disability (ID), and minor dysmorphism, using the Illumina® Infinium Human1M-DuoV1 array. In three patients we found likely causative de novo CNVs, i.e. deletions in 1q41q42.12 (3.4 Mb) and 19p13.2 (834 kb), and a mosaic two-segment duplication in 17p13.2 (218 kb) and 17p13.1 (422 kb). In six additional patients there were aberrations (a deletion in one and duplications in five patients) with uncertain clinical consequences. In total, the finding of causative chromosomal micro-rearrangements in 3 out of 43 patients (7%) and potentially causative CNVs in 6 additional patients (14%) with epilepsy and ID but without major malformations confirms the power of DNA arrays for the detection of new disease-related genetic regions.

De novo combined duplications/inversions are very rare chromosomal rearrangements. For chromosome 7 just some dozen cases of duplications of various parts of the long arm have been published. We report on a 12-year-old boy with muscular hypotonia, global developmental delay, short stature, and various facial dysmorphism including frontal bossing, temporal narrowing, slightly down-slanting palpebral fissures, a broad nasal root, a long philtrum, a thin and tented upper lip, a drooping lower lip, micrognathia, prominent ears, a short neck, and a low posterior hairline. Karyotype analysis and molecular investigations revealed a complex de novo chromosomal rearrangement on 7q. FISH analysis with locus specific YACs and BACs and SNP array with the Illumina(®) HumanOmni1-Quad v1.0 BeadChip disclosed a direct duplication in the long arm of chromosome 7 (q22.1→q32.2) and an inversion located at the breakpoint between the two copies of the duplication (q31.31→q31.33). In addition, breakpoint characterization at the molecular level revealed a 386 bp insertion carrying two Alu elements of chromosome 19p13.2 between the two copies of the duplication. By a comparison of the SNP haplotypes of the derivative chromosome of the patient and both parents a two-step formation during spermatogenesis was suggested as the most likely mechanism of formation.

Idiopathic infantile hypercalcaemia (IIH) is an autosomal recessively inherited disease, presented in the first year of life with hypercalcaemia, precipitated by normal amounts of vitamin D supplementation. Recently loss-of-function mutations in the CYP24A1 gene, which encodes the vitamin D-metabolizing enzyme 24-hydroxylase, have been found in these patients. We describe a young man homozygous for a novel missense mutation (c.628T>C) of the CYP24A1 gene. He had suffered from severe hypercalcaemia in early childhood. At age 29 he presented with medullary nephrocalcinosis, chronic kidney disease (CKD) stage 2, microalbuminuria, mild hypertension and nephrogenic diabetes insipidus. He had mild hypercalcaemia and moderate hypercalciuria. As a novel finding, fibroblast growth factor 23 (FGF23) was elevated.

Most balanced chromosomal aberrations are not associated with a clinical phenotype, however, in some patients they may disrupt gene structure. With the development of various next-generation sequencing techniques, fast and specific analyses of the breakpoint regions of chromosomal rearrangements are possible. Here, we report on a 19-year-old woman with a de novo balanced translocation t(2;8)(p13.2;q22.1) and a severe clinical phenotype including intellectual disability, epilepsy, behavioral features resembling autism, and minor dysmorphic features. By next-generation sequencing, we defined the breakpoints and found disruption of the exocyst complex component 6B (EXOC6B) gene in intron 1 on chromosome 2p13.2 involving two Alu elements with a homology of 81%. No gene was found at the respective breakpoint on chromosome 8. Expression analysis of the EXOC6B in blood lymphocytes and buccal smear revealed reduced expression in the patient in comparison with the control. Our findings in combination with one recently published case and one other patient listed in DECIPHER v5.1 indicate EXOC6B as a gene relevant for intellectual development and electrophysiological stability.

Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.Cell Death and Differentiation advance online publication, 22 July 2016; doi:10.1038/cdd.2016.76.

Multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder is a rare inherited progressive skeletal disorder caused by mutations in the matrix metalloproteinase 2 (MMP2) gene. Treatment options are limited. Herein we present successful bisphosphonate therapy in three affected patients. Patients were treated with bisphosphonates (either pamidronate or zoledronate) for different time periods. The following outcome variables were assessed: skeletal pain, range of motion, bone densitometry, internal medical problems as well as neurocognitive function. Skeletal pain was dramatically reduced in all patients soon after initiation of therapy and bone mineral density increased. Range of motion did not significantly improve. One patient is still able to walk with aids at the age of 14 years. Neurocognitive development was normal in all patients. Bisphosphonate therapy was effective especially in controlling skeletal pain in MONA spectrum disorder. Early initiation of treatment seems to be particularly important in order to achieve the best possible outcome.

Summary Progressive myoclonic epilepsy (PME) is a heterogeneous group of epilepsies characterized by myoclonus, seizures and progressive neurological symptoms. The index patient was a 6-year old boy showing early-onset therapy resistant PME and severe developmental delay. Genome-wide linkage analysis identified several candidate regions. The potassium channel tetramerization domain containing 7 gene (KCTD7) in the 7q11.21 linkage region emerged as a suitable candidate. Sequence analysis revealed a novel homozygous missense mutation (p.R94W) in a highly conserved segment of exon 2. This is the second family with PME caused by KCTD7 mutations, hence KCTD7 mutations might be a recurrent cause of PME.

De novo cytogenetically balanced reciprocal non-Robertsonian translocations are rare findings in clinical cytogenetics and might be associated with an abnormal phenotype. Knowledge of the parental origin and mechanisms of formation is still limited. By microdissection of the derivative chromosomes and their normal homologs from metaphases followed by microsatellite-mediated marker analysis we identified 7 cases of paternal and 3 cases of maternal origin in a cohort of 10 patients with de novo cytogenetically balanced reciprocal non-Robertsonian translocations. Neither in the maternal nor in the paternal group of our study parental age seems to be increased. Together with the data from the literature our results confirm that the majority of de novo cytogenetically balanced reciprocal translocations are of paternal origin, but the preponderance does not appear to be as distinct as previously thought and the paternal age does not seem to be necessarily a major contributing factor.

Background: Williams-Beuren syndrome (WBS) is a developmental disorder with multisystemic manifestations mainly characterized by vascular stenoses, distinctive craniofacial features, mental retardation with a characteristic neurocognitive profile and some endocrine and connective tissue abnormalities, caused by a recurrent deletion of 1.55 Mb including 26-28 genes at chromosomal region 7q11.23. The analysis of clinical-molecular correlations in a few reported atypical patients has been useful to propose several deleted genes as main contributors to specific aspects of the WBS phenotype. Patients and methods: We have studied two additional families with partial phenotypes and atypical 7q11.23 deletions. Deletions were precisely defined at the nucleotide level and expression levels of some affected and flanking genes were assessed in lymphoblastoid cell lines. Results: Affected individuals presented variable cardiovascular and connective tissue manifestations, subtle craniofacial features, normal visuospatial construction abilities with low average IQ and no endocrine abnormalities. The deletion in family NW1 encompassed 817 kb with 11 genes (CLDN3-GTF2IRD1), and 610 kb with 14 genes (VPS37D-RFC2) in family NW2. All deleted genes in typical and atypical deletions revealed low expression levels in lymphoblastoid cell lines, except for GTF2IRD1. CLIP2 was also underexpressed in all patients despite being outside the deletion in NW2, while no other flanking non-deleted gene showed significantly different expression compared to controls. Conclusions: Along with previously reported cases, clinical-molecular correlations in these two families further corroborate that functional hemizygosity for the GTF2I +/- GTF2IRD1 genes is the main cause of the neurocognitive profile and some aspects of the gestalt phenotype of WBS.

Diploid/triploid mosaicism is a rare chromosome aberration characterized by growth and mental retardation, muscular hypotonia, clinodactyly, syndactyly of fingers and toes, asymmetry of the body and the face, truncal obesity, and pigmentary anomalies of the skin. Many patients initially present with severe growth retardation and develop truncal obesity later in life. Variable phenotype expression during development and restriction of triploid cells to certain tissues explain why the diagnosis of diploid/triploid mosaicism is often delayed. Here, we report on a moderately retarded 14-year-old girl with diploid/triploid mosaicism due to inclusion of the second polar body, whose changing phenotype overlaps considerably with different genetic disorders associated with aberrant genomic imprinting. The observation that triploid cells, which in our patient show remarkably variable distribution in different tissues, may also be present in easily accessible tissues such as urinary sediment or buccal smear may contribute to an earlier diagnosis of this rare syndrome.

Objective: To review all cases with segmental and/or complex uniparental disomy (UPD) and to discuss the impact of these cases on Medical Genetics. Design: Searching for published reports in Pubmed and in the abstract books of the annual meetings of the American Society of Human Genetics and the European Society of Human Genetics up to March 2008. Results: In total, 26 cases with segmental UPD and a normal karyotype, 38 cases with UPD of a whole chromosome and a simple reciprocal or non-homologous Robertsonisn translocation, four cases each with two isochromosomes and UPD of the short arm isochromosme and opposite UPD of the long arm isochromosome, three cases with UPD and an isochromosome of the short arm and the long arm of a metacentric or a submetacentric chromosome, one case with maternal UPD and an isochromosome 8 associated with a homozygous deletion (8)(p23.3pter), 42 cases with UPD and an isochromosome of the long arm of an acrocentric chromosome, 33 cases with UPD and a supernumerary marker or ring chromosome, 17 cases with UPD of a whole or parts of a chromosome and a complex karyotype, 13 cases with most likely mosaicism for genome-wide paternal UPD, and 3 cases with most likely mosaicism for genome-wide maternal UPD were found. Conclusion: This update shows that particularly the number of reported cases with segmental UPD or UPD associated with a marker chromosome clearly increased within the last years, and that the investigation of both parents in cases with homozygosity of an autosomal recessively inherited mutation in some cases might help improving genetic counselling coming to a reduced recurrence risk in the case of UPD. Moreover, cases with segmental or complex UPD show that meiosis and early postzygotic mitoses seem to be more complex events than previously thought. For the formation of all kinds of segmental or complex UPD or genome-wide UPD mosaicism always a fortunate cooccurrence of meiotic or mitotic recombination, abnormal segregation, and subsequent correction are necessary. No case of recurrence has been reported until now. Therefore, in subsequent pregnancies invasive prenatal diagnosis is not necessarily indicated.

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:22:37Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:33:38Z : No. of bitstreams: 1 2-s2.0-35349019691.pdf: 4144234 bytes, checksum: 9b86846640bd2e66375c65e289357bd0 (MD5) Made available in DSpace on 2014-05-27T11:22:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-10-24 Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P = .001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified. © 2007 by The American Society of Human Genetics. All rights reserved. Leeds Institute of Molecular Medicine, Leeds DNA Laboratory Department of Clinical Genetics St. James's University Hospital, Leeds Cancer Research UK Mutation Detection Facility, Leeds Department of Paediatric Neurology Leeds General Infirmary, Leeds Department of Paediatric Neurology Erasme Hospital, Brussels Children's Hospital Queen Fabiola, Brussels Service de Neuropédiatrie Hôpital Trousseau Department of Paediatric Neurology Hôpital Trousseau Pediatric Neurology Department Hôpital Bicêtre Institut de Myologie Groupe Hospitalier Pitié-Salpêtrière Service de Virologie Hôpital Cochin-St. Vincent de Paul, Paris Department of Clinical Biochemistry Hospital Sant Joan de Déu-Ciberer, Barcelona Department of Barcelona Pediatric Neurology Hospital Sant Joan de Déu-Ciberer, Barcelona Department of Paediatrics St. Luke's Hospital, Guardamangia Department of Molecular and Human Genetics Baylor College of Medicine, Houston Serive de Neurologie Centre Hospitalier, Pau Department of Paediatrics Children's Hospital, Sheffield Developmental and Metabolic Neurology Branch National Institute of Neurological Disorders and Stroke National Institutes of Health, Bethesda Department of Human Genetics Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen Unit of Molecular Medicine Bambino Gesù Children's Research Hospital, Rome Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Casa Sollievo Della Sofferenza Mendel Institute, Rome Muscular and Neurodegenerative Disease Unit G. Gaslini Institute, Genova Department of Clinical Genetics Churchill Hospital, Oxford Division of Clinical Chemistry and Biochemistry University Children's Hospital, Zurich Clinical Genetics Unit Birmingham Women's Hospital, Birmingham Department of Paediatrics Sandwell and West Birmingham NHS Trust, Birmingham Neurology Department Birmingham Children's Hospital, Birmingham Department of Human Genetics Radboud University, Nijmegen Department of Pediatric Neurology Radboud University, Nijmegen Department of Paediatric Neurology Royal Children's Hospital, Brisbane, QLD Genetic Health Queensland Royal Children's Hospital, Brisbane, QLD Serviço de Aconselhamento Genético Universidade Estadual de São Paulo, Botucatu Academic Unit of Medical Genetics St. Mary's Hospital, Manchester Kinderkrankenhaus Auf der Bult, Hannover Department of Paediatrics Bradford National Health Service (NHS) Trust, Bradford Developmental Neurology Department Fondazione Istituto Neurologico C. Besta, Milan Grampian Clinical Genetics Centre, Aberdeen Department of Neonatology University Hospital, Ghent Department of Pediatrics University Hospital, Ghent Department of Clinical Genetics Maastricht University Hospital, Maastricht Department of Neurology Maastricht University Hospital, Maastricht Department of Paediatrics and Imaging Sciences Imperial College Great Ormond Street Hospital, London St. Mary's NHS Trust Great Ormond Street Hospital, London Department of Ophthalmology Great Ormond Street Hospital, London North East Thames Regional Genetics Service Great Ormond Street Hospital, London Evelina Children's Hospital Guy's and St. Thomas' NHS Trust, London Department of Paediatrics Université Laval Medical School, Québec Clinical Genetics Unit Hospital de Cruces, Baracaldo Service de Génétique Médicale Centre Hospitalier Universitaire Pellegrin Enfants, Bordeaux Unité de Neurologie de l'Enfant et de l'Adolescent Centre Hospitalier Universitaire Pellegrin Enfants, Bordeaux National Centre for Medical Genetics Our Lady's Hospital, Dublin Department of Paediatric Neurology Children's University Hospital, Dublin Department of Medical Genetics Rikshospitalet-Radiumhospitalet, Oslo Department of Paediatrics Rikshospitalet-Radiumhospitalet, Oslo Rikshospitalet-Radiumhospitalet, Oslo Department of Pediatrics Academic Medical Center, Amsterdam Department of Child Neurology Vrije Universiteit Medical Center, Amsterdam Medical Research Council Human Genetics Unit Western General Hospital, Edinburgh Department of Clinical Genetics Leiden University Medical Center, Leiden Division of Pediatric Neurology Oregon Health and Science University, Portland, OR Pediatric Neurology Klinikum Aschaffenburg, Aschaffenburg Department of Neurology Royal Children's Hospital, Parkville, Vic. Division of Clinical Genetics Department for Medical Genetics Medical University Innsbruck, Innsbruck Department of Pediatrics Division of Pediatric Neurology and Inborn Errors of Metabolism Children's Hospital Innsbruck, Innsbruck Klinik für Kinder und Jugendliche, Konstanz Paediatric Neurology University Hospitals of Gasthuisberg, Leuven Department of Child Neurology and Psychiatry IRCCS Casimiro Mondino Institute of Neurology, Pavia Department of Neurogenetics School of Medicine of Ribeirao Preto, Ribeirao Preto Greenwood Genetic Center, Greenwood, SC Raphael Recanati Genetic Institute Rabin Medical Center, Petach-Tikva Department of Paediatrics Crosshouse Hospital, Ayr Fraser of Allander Neurosciences Unit Royal Hospital for Sick Children, Glasgow Duncan Guthrie Institute of Medical Genetics Royal Hospital for Sick Children, Glasgow Division of Medical Genetics Montreal Children's Hospital, Montreal Department of Paediatric Neurology University Hospitals of Leicester NHS Trust, Leicester University Hospital of Aarhus, Aarhus Division of Pediatric Dermatology British Columbia's Children's Hospital, Vancouver, BC Institut de Pathologie et de Génétique, Gosselies Pediatric Neurology Department Guide Chauliac Hospital, Montpellier Servicio de Pediatría Hospital Universitario Doctor Peset, Valencia Genetic Institute Ha'Emek Medical Center, Afula Rappaport Faculty of Medicine Technion, Haifa Neuropediatrics Unit Complejo Hospitalario de Jean, Jean Department of Paediatrics Manor Hospital, Walsall Division of Neuropediatrics University Hospital, Freiburg Genetic Health Services Victoria Royal Children's Hospital, Vic. Service de Génétique Hôpital Debrousse, Lyon Lancashire Teaching Hospitals Trust, Preston Neonatal Intensive Care Unit Arcispedale Santa Maria Nuova, Reggio Emilia Center for Medical Genetics, Antwerp Department of Neurology Children's National Medical Center, Washington, DC Department of Neuropediatrics Humboldt University, Berlin Leeds Institute of Molecular Medicine St. James's University Hospital Wellcome Trust Brenner Building, Leeds LS9 7TF Serviço de Aconselhamento Genético Universidade Estadual de São Paulo, Botucatu

Pseudoisodicentric or asymmetrical dicentric chromosomes 18 are rare findings in clinical cytogenetics. So far, only 8 patients with breakpoints in 18q have been reported and in none of them breakpoints were narrowed down to the molecular level. Here, we describe a 17 months old girl with a perimembranous ventricular septal defect, cleft palate, and minor dysmorphism including hypertelorism, flat nose, frontal bossing and low set ears as well as mosaicism for a cell line with a pseudoisodicentric chromosome 18q and a second cell line with a terminal deletion of 11 Mb in 18q22.2→qter. SNP-array investigation revealed a symmetric breakpoint in 18q22.2 and most likely postzygotic formation from the maternal chromosome 18. Clinical findings in all patients reported so far as well as in the patient presented here were in part overlapping with the clinical phenotypes of trisomy 18 and partial monosomy 18q.

Chromosomal mosaicism is the presence of numerous cell lines with different chromosomal complements in the same individual. Uniparental disomy (UPD) is the inheritance of two homologous chromosomes from the same parent. These genetic anomalies arise from errors in meiosis and/or mitosis and can occur independently or in combination. Due to the formation mechanisms of UPD, low-level or undetected mosaicisms are assumed for a significant number of UPD cases. The pre- and postnatal clinical consequences of mosaicism for chromosomal aberrations and/or UPD depend on the gene content of the involved chromosome. In prenatal evaluation of chromosomal mosaicism and UPD, genetic counseling should be offered before any laboratory testing.

We report on a pair of dizygotic twin boys born after ICSI. One twin was affected with maternal meiosis I-derived free trisomy 21. The other had multiple congenital malformations including a complex heart defect and oesophageal atresia. The advanced maternal age of 37 years predisposed for chromosome 21 meiosis I non-disjunction in twin A. Each of the multiple congenital anomalies in twin B has been described in trisomy 21. However, due to dizygosity demonstrated by a panel of molecular markers mapped on chromosome 21 as well as the results of investigations with 16 short tandem repeat markers localized on various other chromosomes, low level mosaicism or chimerism for this aneuploidy in twin B is unlikely. In addition, the twinning process, which by itself is associated with an increased rate of congenital malformations particularly affecting heart and oesophagus, might be responsible for the multiple congenital anomalies in twin B. Thus, in agreement with the results of several population-based studies from the literature, it appears unlikely that the micromanipulation of ICSI is causally responsible for the different anomalies found in these two boys.

Background Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness. Methods and results Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ∼506 ms with notched T waves). Parents were I° cousins - both heterozygous for the mutation and clinically unremarkable (QTc ∼447 ms, father and ∼396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q. Conclusion Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.

OBJECTIVE—To review all cases with segmental and/or complex uniparental disomy (UPD), to study aetiology and mechanisms of formation, and to draw conclusions. DESIGN—Searching published reports in Medline. RESULTS—The survey found at least nine cases with segmental UPD and a normal karyotype, 22 cases with UPD of a whole chromosome and a simple or a non-homologous Robertsonian translocation, eight cases with UPD and two isochromosomes, one of the short arm and one of the long arm of a non-acrocentric chromosome, 39 cases with UPD and an isochromosome of the long arm of two homologous acrocentric chromosomes, one case of UPD and an isochromosome 8 associated with a homozygous del(8)(p23.3pter), and 21 cases with UPD of a whole or parts of a chromosome associated with a complex karyotype. Segmental UPD is formed by somatic recombination (isodisomy) or by trisomy rescue. In the latter mechanism, a meiosis I error is associated with meiotic recombination and an additional somatic exchange between two non-uniparental chromatids. Subsequently, the chromatid that originated from the disomic gamete is lost (iso- and heterodisomy). In cases of UPD associated with one isochromosome of the short arm and one isochromosome of the long arm of a non-acrocentric chromosome and in cases of UPD associated with a true isochromosome of an acrocentric chromosome, mitotic complementation is assumed. This term describes the formation by misdivision at the centromere during an early mitosis of a monosomic zygote. In cases of UPD associated with an additional marker chromosome, either mitotic formation of the marker chromosome in a trisomic zygote or fertilisation of a gamete with a marker chromosome formed in meiosis by a disomic gamete or by a normal gamete and subsequent duplication are possible. CONCLUSIONS—Research in the field of segmental and/or complex UPD may help to explain undiagnosed non-Mendelian disorders, to recognise hotspots for meiotic and mitotic recombinations, and to show that chromosomal segregation is more complex than previously thought. It may also be helpful to map autosomal recessively inherited genes, genes/regions of genomic imprinting, and dysmorphic phenotypes. Last but not least it would improve genetic counselling. Keywords: genomic imprinting; isochromosome; Robertsonian translocation; uniparental disomy (UPD)

Intrauterine growth retardation (IUGR) is defined as length and/or weight below the 10th percentile. Etiology and, consequently, long-term outcome are extremely heterogeneous with chromosomal abnormalities found in up to 7%. Recently, uniparental disomy (UPD), i.e. the inheritance of both homologues of one pair of chromosomes from only one parent, was found in an increasing number of children with IUGR. Particularly, UPD of chromosome 7 was found in up to 10% of patients with IUGR and/or a phenotype of primordial growth retardation or Silver-Russell syndrome (SRS), but also UPD of chromosomes 2, 6, 14, 16, 20, and 22 was reported in single cases with IUGR. To evaluate impact and relevance of UPD in children with IUGR we investigated 23 sporadic cases with IUGR subsequently diagnosed as primordial growth retardation (n = 13) or SRS (n = 10) by molecular methods for UPD of chromosomes 2, 6, 14, 16, 20, and 22. No instance of UPD was found. Inheritance of all chromosomes investigated was biparental in all cases. Therefore, we conclude that UPD of these chromosomes is not a major cause of IUGR.

Mosaicism for a derivative 21, der(21;21)(q10;q10), is a rare chromosomal abnormality. Since a normal cell line is present, mitotic origin is considered. Chromosome examination of a female with developmental delay and dysmorphic features compatible with mosaic trisomy 21 revealed a normal cell line and a second cell line with a der(21;21)(q10;q10) [46,XX/46,XX,der(21;21)(q10;q10),+21]. Molecular investigation with a panel of highly polymorphic microsatellites mapping to chromosome 21 demonstrated three different alleles, two of paternal and one of maternal origin. Therefore, either formation of the der(21;21)(q10;q10) during paternal meiosis with subsequent loss of the der(21;21)(q10;q10) and mitotic reduplication of the maternal homologue in the normal cell line, or more likely a zygote with paternally derived trisomy 21 and subsequent mitotic formation of the der(21;21)(q10;q10) have to be considered. This case again shows that mammalian chromosome aberrations may have a more complex mechanism of formation than was previously thought.

Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein.

Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A. Here, we report on overlapping microdeletions at Xq24 that do not include UBE2A or affect its expression, in patients with non-syndromic ID plus some additional features from three unrelated families. The smallest region of overlap, confirmed by junction sequencing, harbors two members of the mitochondrial solute carrier family 25, SLC25A5 and SLC25A43. However, identification of an intragenic microdeletion including SLC25A43 but not SLC25A5 in a healthy boy excluded a role for SLC25A43 in cognition. Therefore, our findings point to SLC25A5 as a novel gene for non-syndromic ID. This highly conserved gene is expressed ubiquitously with high levels in cortex and hippocampus, and a presumed role in mitochondrial exchange of ADP/ATP. Our data indicate that SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions.

Interstitial duplications of the short arm of chromosome 2 have been rarely described. Here, we report on two unrelated patients with overlapping chromosome 2p16 → p22 de novo microduplications found by SNP-array analysis. The affected individuals were an 8-year-3-month-old boy with a direct duplication of approximately 14.6 Mb harboring 63 genes, and a 12-year-old girl with a direct duplication of around 9.6 Mb harboring 48 genes. Both patients have severe growth retardation, delayed bone age, prominent veins on trunk and extremities, total IGF1 level in the low range, mild developmental delay, and facial dysmorphism such as relative macrocephaly, a broad and prominent forehead, and a large anterior fontanelle. Comparison with patients previously reported in the literature and in the DECIPHER 5.1 and ECARUCA databases indicates a common region of interest of around 1.9 Mb responsible for most of the features. Two candidate genes (EPAS and RHOQ), may be particularly relevant for the marked growth retardation and developmental delay.

Objective To study genotype–phenotype correlation of ring chromosome 18 [r(18)] in 9 patients with 46,XN karyotype. Study design In 9 patients with a de novo 46,XN,r(18) karyotype (7 females, 2 males), we performed high-resolution single-nucleotide polymorphism array analysis (Illumina Human Omni1-QuadV1 array in 6 patients, Affymetrix 6.0 array in 3 patients), investigation of parental origin, and genotype–phenotype correlation. Results No breakpoint was recurrent. Single metaphases with loss of the ring, double rings, or secondarily rearranged rings were found in some cases, but true mosaicism was present in none of these cases. In 3 patients, additional duplications in 18p (of 1.4 Mb, 2 Mb, and 5.8 Mb) were detected. In 1 patient, an additional deletion of 472 kb in Xp22.33, including the SHOX gene, was found. Parental origin of r(18) was maternal in 2 patients and paternal in 4 patients, and formation was most likely meiotic. Karyotype was normal in all investigated parents (n = 15). At birth, mean maternal age was 30 years (n = 9) and mean paternal age was 34.4 years (n = 9). Conclusion Genotype–phenotype correlation revealed extensive clinical variability but no characteristic r(18) phenotype. Severity of clinical signs were generally correlated with the size of the deletion. Patients with large deletions in 18p and small deletions in 18q exhibited mainly symptoms related to 18p-, whereas those with large deletions in 18q and small deletions in 18p had symptoms of 18q-.

Maternal uniparental disomy for the entire chromosome 7 has so far been reported in three patients with intrauterine and postnatal growth retardation. Two were detected because they were homozygous for a cystic fibrosis mutation for which only the mother was heterozygous, and one because he was homozygous for a rare COL1A2 mutation. We investigated 35 patients with either the Silver-Russell syndrome or primordial growth retardation and their parents with PCR markers to search for uniparental disomy 7. Four of 35 patients were found to have maternal disomy, including three with isodisomy and one with heterodisomy. The data confirm the hypothetical localization of a maternally imprinted gene (or more than one such gene) on chromosome 7. It is suggested to search for UPD 7 in families with an offspring with sporadic Silver-Russell syndrome or primordial growth retardation.

Objective To identify copy number variations (CNVs) as a hint toward genes relevant for spermatogenesis and related to male factor infertility. Design Analysis of genomic DNA with high resolution Illumina SNP arrays (HumanOmni1-Quad Bead Chip). Sanger sequencing of the CLCA4 gene in all patients of the study. Analysis of CLCA4 expression in various human tissue samples. Setting University department. Patient(s) A total of 39 infertile men with idiopathic infertility ranging from oligoasthenoteratozoospermia to azoospermia. Intervention(s) None. Main Outcome Measure(s) Copy number variations more than 10 kb. Result(s) We detected a heterozygous deletion including exons 4–9 of the CLCA4 gene in one man with cryptozoospermia, as well as a total of 149 CNVs not yet reported in various databases and carrying 200 protein coding genes in the 39 men. Conclusion(s) According to our results CLCA4 is apparently expressed in postmeiotic germ cells and somatic cells. We therefore conclude that CLCA4 might be functional during human spermatogenesis after meiosis, most likely as a modifier of CFTR gene expression. CLCA4 can thus be considered as a novel dominant germ line gene potentially causing male factor infertility if functionally disrupted. Our study demonstrates the power of DNA arrays to identify novel CNVs carrying candidate genes causing male factor infertility.

Rostasy K, Fauth C, Gautsch K, Laimer I, Krabichler B, Wimmer K, Fruhmesser A, Kotzot D, Moshir S. Modification of risk for cancer as a coincidental finding in DNA array investigation. The high resolution of modern DNA arrays has the implification of unintended coincidental detection of gene deletions predisposing to late-onset neurological and oncological disorders. Here, we report the case of an 18-year-old girl with mild intellectual disability, facial dysmorphisms, and a microdeletion of approximately 6.3 Mb on 22q12.1q12.3 including NF2, the gene for neurofibromatosis type 2, and CHEK2, a modifier gene for breast cancer. Subsequent magnetic resonance imaging of the brain showed she had already developed bilateral vestibular schwannomas. The challenge of DNA arrays and the consequences for genetic counselling and informed consent will be discussed in the light of this unique case with a microdeletion including both a high risk and a moderate risk cancer predisposition gene.

Kohlschütter-Tönz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta. The molecular basis has not yet been elucidated. Here, we report that KTS is caused by mutations in ROGDI. Using a combination of autozygosity mapping and exome sequencing, we identified a homozygous frameshift deletion, c.229_230del (p.Leu77Alafs(∗)64), in ROGDI in two affected individuals from a consanguineous family. Molecular studies in two additional KTS-affected individuals from two unrelated Austrian and Swiss families revealed homozygosity for nonsense mutation c.286CT (p.Gln96(∗)) and compound heterozygosity for the splice-site mutations c.531+5GC and c.532-2AT in ROGDI, respectively. The latter mutation was also found to be heterozygous in the mother of the Swiss affected individual in whom KTS was reported for the first time in 1974. ROGDI is highly expressed throughout the brain and other organs, but its function is largely unknown. Possible interactions with DISC1, a protein involved in diverse cytoskeletal functions, have been suggested. Our finding that ROGDI mutations cause KTS indicates that the protein product of this gene plays an important role in neuronal development as well as amelogenesis.

Complex chromosomal rearrangements (CCRs) are rare findings in clinical cytogenetics. As a result of the high risk of unbalanced segregation, familial cases are even rarer and maternal transmission occurs more frequently than paternal transmission. Analogous to Drosophila and mice, as well as to CCRs involving the Y chromosome or a clinically relevant associated deletion, a preferential origin in spermatogenesis has been assumed but not proven directly and systematically thus far. Here, we investigated three healthy adults, one healthy child, and one child with multiple congenital anomalies and various balanced de novo CCRs. The analyses were performed in each case on 10 copies of a derivative chromosome and their normal homologs by glass-needle microdissection, whole genome amplification (WGA), and microsatellite-mediated haplotype analysis. With respect to the number of chromosomes involved in each case and in all cases together, the number of chromosomal segments in each case and in all cases together, and the number of breakpoints in each case and in all cases together, the conformity for paternal origin of all derivative chromosomes and maternal origin of their normal homologs makes formation in paternal germline more likely than a postzygotic formation with an accidental uniformity. In conclusion, our results confirm the preferential formation of de novo balanced CCRs in the paternal germline.

Contains fulltext : 88233.pdf (Publisher’s version ) (Closed access) Cleidocranial Dysplasia (CCD) is an autosomal dominant skeletal disorder characterized by hypoplastic or absent clavicles, increased head circumference, large fontanels, dental anomalies, and short stature. Hand malformations are also common. Mutations in RUNX2 cause CCD, but are not identified in all CCD patients. In this study we screened 135 unrelated patients with the clinical diagnosis of CCD for RUNX2 mutations by sequencing analysis and demonstrated 82 mutations 48 of which were novel. By quantitative PCR we screened the remaining 53 unrelated patients for copy number variations in the RUNX2 gene. Heterozygous deletions of different size were identified in 13 patients, and a duplication of the exons 1 to 4 of the RUNX2 gene in one patient. Thus, heterozygous deletions or duplications affecting the RUNX2 gene may be present in about 10% of all patients with a clinical diagnosis of CCD which corresponds to 26% of individuals with normal results on sequencing analysis. We therefore suggest that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation. 01 augustus 2010

Objective To describe the parental origin and the mechanism of formation of an 47,XY,idic(X)(p11.2) karyotype in a patient with Klinefelter syndrome. Design Case report. Setting A university hospital. Patient(s) A 36-year-old man with primary infertility. Intervention(s) Genotype–phenotype correlation and microsatellite marker-mediated haplotype analysis subsequent to whole genome amplification of microdissected chromosomes. Main Outcome Measure(s) Genotype–phenotype correlation, mechanism of formation, and parental origin. Result(s) Maternal origin of the isochromosome and the normal X chromosome and loss of maternal heterozygosity for all informative Xq markers on the isochromosome and in each case, the presence of the other maternal allele on the normal homologue was shown. Comparative analysis of the clinical features of 17 additional cases and of 1 case with a 46,XY/47,XY,i(X)(q10) karyotype reported in the literature revealed a phenotype very similar to the clinical findings in patients with a 47,XXY karyotype. Conclusion(s) The molecular results in our patient indicate a maternal origin of a true dicentric isochromosome and most likely postzygotic formation subsequent to a nondisjunction in maternal meiosis II. With the exception of the final height the phenotype of Klinefelter syndrome appears not to be the consequence of trisomy of the pseudoautosomal region on Xp.

Maternal uniparental disomy (UPD) 7 is found in approximately 5% of patients with Silver-Russell syndrome. By a descriptive and comparative clinical analysis of all published cases (more than 60 to date) their phenotype is updated and compared with the clinical findings in patients with Sliver-Russell syndrome (SRS) of either unexplained etiology or epimutations of the imprinting center region 1 (ICR1) on 11p15. The higher frequency of relative macrocephaly and high forehead/frontal bossing makes the face of patients with epimutations of the ICR1 on 11p15 more distinctive than the face of cases with SRS of unexplained etiology or maternal UPD 7. Because of the distinct micrognathia in the latter, their triangular facial gestalt is more pronounced than in the other groups. However, solely by clinical findings patients with maternal UPD 7 cannot be discriminated unambiguously from patients with epimutations of the ICR1 on 11p15 or SRS of unexplained etiology. Therefore, both loss of methylation of the ICR1 on 11p15 and maternal UPD 7 should be investigated for if SRS is suspected.

Cohen syndrome (CS) is an autosomal recessive disorder with variability in the clinical manifestations, characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in the gene COH1 have been found in an ethnically diverse series of patients. Brief clinical descriptions of 24 patients with CS are provided. The patients were from 16 families of different ethnic backgrounds and between 2.5 and 60 years of age at assessment. DNA samples from all patients were analysed for mutations in COH1 by direct sequencing. Splice site mutations were characterised using reverse transcriptase PCR analysis from total RNA samples. In this series, we detected 25 different COH1 mutations; 19 of these were novel, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in frame deletions, and 1 missense mutation. We observed marked variability of developmental and growth parameters. The typical facial gestalt was seen in 23/24 patients. Early onset progressive myopia was present in all the patients older than 5 years. Widespread pigmentary retinopathy was found in 12/14 patients assessed over 5 years of age. We present evidence for extended allelic heterogeneity of CS, with the vast majority of mutations leading to premature termination codons in COH1. Our data confirm the broad clinical spectrum of CS with some patients lacking even the characteristic facial gestalt and pigmentary retinopathy at school age.

Infantile spinal muscular atrophy (SMA) is a common autosomal recessive disease with a high demand for carrier testing. The disease is caused by homozygous deletions of the survival motor neuron (SMN)1 gene on chromosome 5q13 in more than 90% of cases. Meanwhile, several reliable quantitative methods for carrier detection in the general population have been implemented with a risk of at least 5% for false negative results. Linkage analyses with chromosome 5 markers can be used for complementary information, but they are restricted to risk estimation of close relatives in affected families. Here, we present the first observation of a somatic mosaicism in an SMA carrier. Molecular genetic studies gave evidence that the SMN1 deletion of an SMA type I patient most probably arose from somatic mosaicism in the paternal grandmother. The patient's father and his two brothers were shown to be carriers of three different maternal haplotypes in 5q13. Final conclusions for genetic counselling were only possible after both linkage analysis and quantitative real-time PCR analysis of SMN1 copy numbers.

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. Meiotic nondisjunction followed by trisomy rescue is considered to be the major mechanism of formation. A literature search for cases with whole chromosome UPD other than UPD 15 was performed. Information on parental age was available in 111 cases with maternal UPD and in 34 cases with paternal UPD. In 52 out of 74 cases with maternal heterodisomy, information on the time of nondisjunction was also available. Around two-thirds of these cases were due to a maternal meiosis I error. Compared with the mean maternal age of 30.0 years in Bavarian mothers, in the year 2000 an advanced mean maternal age of 34.8 years was found in cases with maternal heterodisomy (n=74; P

Objectives To localize the gene that causes an autosomal recessively inherited vitreoretinal dystrophy that has not been described, to our knowledge, and to analyze a candidate gene mapped to 22q13 (fibulin-1 [ FBLN1 ]). Methods Homozygosity mapping with 500 microsatellite markers spread over the whole genome (mean distance, 7.2 centimorgans [c M]) and mutation analysis of the complete coding region of FBLN1 . Results Homozygosity for all analyzed markers was found in the 4 affected siblings in a region on chromosome 22 encompassing 12 c M from D22S444 (centromeric) to D22S1170 (telomeric). Lod scores were between 0.017 and 2.36 (theta = 0). A mutation analysis of the complete coding region of FBLN1 , which encodes interacting extracellular matrix proteins, revealed 4 previously undescribed single nucleotide polymorphisms. Conclusions A genomewide homozygosity mapping analysis supported the hypothesis that the gene responsible for a unique vitreoretinal dystrophy is located on chromosome 22q13. No obviously pathogenic mutation was found in the candidate gene, FBLN1 .

Objectives To describe the clinical phenotype of a novel autosomal recessively inherited vitreoretinal dystrophy in one generation of a family originating from eastern Switzerland. Methods A clinical study including electroretinographic investigations followed by laboratory-based genetic and molecular analysis. Four affected and 3 unaffected members of the family were examined. Ten candidate regions were tested by linkage analysis with highly polymorphic molecular markers or with intragenic restriction fragment length polymorphisms. Results Of 8 siblings, 4 were affected, showing high myopia with pronounced vitreous liquefaction, retinitis pigmentosa–like retinal degeneration, diffuse retinal pigment epithelium atrophy, macular staphylomata, and premature cataract formation. Strikingly abnormal results on electroretinograms, affecting both the rod and the cone systems, revealed an extensive defect of retinal function, unlike those usually found in pathologic myopia. No extraocular manifestations were observed. Three types of nonsyndromic high myopia, Stickler syndrome I, II, and III, Wagner syndrome, Knobloch syndrome, Goldmann-Favre dystrophy, and multiple vitreoretinopathies were excluded by linkage analysis. Conclusions The reported phenotype as well as the results of molecular linkage analysis in the siblings described here suggest an autosomal recessively inherited vitreoretinal dystrophy, which, to our knowledge, has not been described until now.

Editor—At least 168 cases with a supernumerary marker chromosome (SMC) from all chromosomes not including chromosome 15 have been documented.1 Birth prevalence is estimated at 0.14 to 0.72 per 1000.2 Subjects with a SMC have a partial trisomy (duplication) and in some cases a partial tetrasomy (triplication) of the genetic material contained in the SMC. The risk of an abnormal phenotype associated with a randomly ascertained de novo SMC derived from acrocentric autosomes (excluding chromosome 15) is estimated to be approximately 7% compared with approximately 28% for SMCs derived from non-acrocentric autosomes.1 The great variability of clinical findings in patients with SMCs originating from the same chromosome is probably the result of variation in size and genetic content, the degree of mosaicism, and uniparental disomy of the normal homologues of the chromosome from which the SMC derived. Evidence that subjects with SMCs might have an increased risk for UPD of the structurally normal homologues of the SMCs has been reported by several authors. To the best of our knowledge the coexistence of SMCs with UPD has been described for chromosomes 6, 7, 15, 20, and X.3-7 Here, we describe a further patient with multiple congenital anomalies, developmental delay, and the unique finding of coexistence of SMC 1 mosaicism and maternal uniparental disomy 1. The female patient was born at term after an uneventful pregnancy. At her birth, her mother was 33 years old and her father was 47 years old. Birth weight was 2500 g and length 49 cm. At the age of 6 years, she was investigated because of mental retardation. Height (1.14 m) and weight (17 kg) were within the normal range, but head circumference (44 cm) was far below the 3rd centile. Additional findings were temporal narrowing, downward slanting palpebral fissures, …