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Whereas the vast majority of osteogenesis imperfecta (OI) is caused by autosomal dominant defects in the genes encoding type I procollagen, mutations in a myriad of genes affecting type I procollagen biosynthesis or bone formation and homeostasis have now been associated with rare autosomal recessive OI forms. Recently, homozygous or compound heterozygous mutations in BMP1, encoding the metalloproteases bone morphogenetic protein-1 (BMP1) and its longer isoform mammalian Tolloid (mTLD), were identified in 5 children with a severe autosomal recessive form of OI and in 4 individuals with mild to moderate bone fragility. BMP1/mTLD functions as the procollagen carboxy-(C)-proteinase for types I to III procollagen but was also suggested to participate in amino-(N)-propeptide cleavage of types V and XI procollagens and in proteolytic trimming of other extracellular matrix (ECM) substrates. We report the phenotypic characteristics and natural history of 4 adults with severe, progressive OI characterized by numerous fractures, short stature with rhizomelic shortening, and deformity of the limbs and variable kyphoscoliosis, in whom we identified novel biallelic missense and frameshift mutations in BMP1. We show that BMP1/mTLD-deficiency in humans not only results in delayed cleavage of the type I procollagen C-propeptide but also hampers the processing of the small leucine-rich proteoglycan prodecorin, a regulator of collagen fibrillogenesis. Immunofluorescent staining of types I and V collagen and transmission electron microscopy of the dermis show impaired assembly of heterotypic type I/V collagen fibrils in the ECM. Our study thus highlights the severe and progressive nature of BMP1-associated OI in adults and broadens insights into the functional consequences of BMP1/mTLD-deficiency on ECM organization.

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS. © 2012 The American Society of Human Genetics.

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

Frontometaphyseal dysplasia is an X-linked trait primarily characterized by a skeletal dysplasia comprising hyperostosis of the skull and modeling anomalies of the tubular bones. Extraskeletal features include tracheobronchial, cardiac, and urological malformations. A proportion of individuals have missense mutations or small deletions in the X-linked gene, FLNA. We report here our experience with comprehensive screening of the FLNA gene in a group of 23 unrelated probands (11 familial instances, 12 simplex cases; total affected individuals 32) with FMD. We found missense mutations leading to substitutions in the actin-binding domain and within filamin repeats 9, 10, 14, 16, 22, and 23 of filamin A in 13/23 (57%) of individuals in this cohort. Some mutations present with a male phenotype that is characterized by a severe skeletal dysplasia, cardiac, and genitourinary malformations that leads to perinatal death. Although no phenotypic feature consistently discriminates between females with FMD who are heterozygous for FLNA mutations and those in whom no FLNA mutation can be identified, there is a difference in the degree of skewing of X-inactivation between these two groups. This observation suggests that locus heterogeneity may exist for this disorder.

We report a 19-year-old, non-Amish Caucasian female patient with primary amenorrhea caused by complete lack of Mullerian fusion with vaginal agenesis or Mullerian aplasia (MA), postaxial polydactyly (PAP), and tetralogy of Fallot. The genital tract anomaly of MA with and without renal or skeletal anomalies comprises Mayer-Rokitansky-Kuster-Hauser syndrome, which has not been reported with tetralogy of Fallot. The phenotypic triad of anomalies most closely resembled McKusick-Kaufman syndrome (MKS; OMIM 236700), a rare multiple congenital anomaly syndrome comprised of hydrometrocolpos (HMC), PAP, and congenital heart malformation that is inherited in an autosomal recessive pattern. While upper reproductive tract anomalies have not been reported with MKS, they have been reported with Bardet-Biedl syndrome (BBS), a syndrome that significantly overlaps with MKS. Both MKS and BBS can be caused by mutations in the MKKS or BBS6 gene on chromosome 20p12 and BBS is also associated with mutations in other genes (BBS1, BBS2, BBS4, and BBS7). To address this heterogenity, we sequenced the causative genes in MKS and BBS but no mutations in these five genes were identified. Fluorescence in situ hybridization (FISH) excluded large deletions of chromosome 20p12 and microsatellite marker studies confirmed biparental inheritance for all of the known BBS loci. The dual midline fusion defects of tetralogy of Fallot and MA suggests that either this patient has a unique syndrome with a distinct genetic etiology or that she has a genetically heterogeneous or variant form of MKS.

Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterised by profound congenital sensorineural deafness and prolongation of the QT interval on the electrocardiogram, representing abnormal ventricular repolarisation. In a study of ten British and Norwegian families with JLNS, we have identified all of the mutations in the KCNQ1 gene, including two that are novel. Of the nine mutations identified in this group of 10 families, five are nonsense or frameshift mutations. Truncation of the protein proximal to the recently identified C-terminal assembly domain is expected to preclude assembly of KCNQ1 monomers into tetramers and explains the recessive inheritance of JLNS. However, study of a frameshift mutation, with a dominant effect phenotypically, suggests the presence of another assembly domain nearer to the N-terminus.

We report fluorescence in situ hybridization (FISH) mapping of 152, mostly de novo, apparently balanced chromosomal rearrangement (ABCR) breakpoints in 76 individuals, 30 of whom had no obvious phenotypic abnormality (control group) and 46 of whom had an associated disease (case group). The aim of this study was to identify breakpoint characteristics that could discriminate between these groups and which might be of predictive value in de novo ABCR (DN-ABCR) cases detected antenatally. We found no difference in the proportion of breakpoints that interrupted a gene, although in three cases, direct interruption or deletion of known autosomal-dominant or X-linked recessive Mendelian disease genes was diagnostic. The only significant predictor of phenotypic abnormality in the group as a whole was the localization of one or both breakpoints to an R-positive (G-negative) band with estimated predictive values of 0.69 (95% CL 0.54-0.81) and 0.90 (95% CL 0.60-0.98), respectively. R-positive bands are known to contain more genes and have a higher guanine-cytosine (GC) content than do G-positive (R-negative) bands; however, whether a gene was interrupted by the breakpoint or the GC content in the 200 kB around the breakpoint had no discriminant ability. Our results suggest that the large-scale genomic context of the breakpoint has prognostic utility and that the pathological mechanism of mapping to an R-band cannot be accounted for by direct gene inactivation.

Townes-Brocks syndrome is an autosomal dominantly inherited disorder, which comprises multiple birth defects including renal, ear, anal, and limb malformations. TBS has been shown to result from mutations in SALL1, a human gene related to the developmental regulator SAL of Drosophila melanogaster. The SALL1 gene product is a zinc finger protein thought to act as a transcription factor. It contains four highly conserved, evenly distributed C2H2 double zinc finger domains. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL1 contains a C2HC motif. Most mutations causing TBS are clustered in the N-terminal third of the SALL1 coding region and result in the production of truncated proteins containing only one or none of the C2H2 domains and the N-terminal transcriptional repressor domain of SALL1. Twenty-three SALL1 mutations were reported prior to this work, 22 of which are located in exon 2, 5′ of the second double zinc finger-encoding region. Here we present 12 novel mutations in SALL1 associated with Townes-Brocks syndrome in 13 unrelated families. These include three nonsense mutations, three short insertions and six short deletions. Thus the number of SALL1 mutations increases to 35. Rare phenotypical features among mutation positive patients include hypothyroidism, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadia scrotalis, unilateral chorioretinal coloboma with loss of vision, dorsal hypoplasia of the corpus callosum, and umbilical hernia. © 2005 Wiley-Liss, Inc.

Genomewide linkage searches aimed at identifying disease susceptibility loci are generally conducted using 300–400 microsatellite markers. Genotyping bi-allelic single nucleotide polymorphisms (SNPs) provides an alternative strategy. The availability of dense SNP maps coupled with recent technological developments in highly paralleled SNP genotyping makes it practical to now consider the use of these markers for whole-genome genetic linkage analyses. Here, we report the findings from three successful genomewide linkage analyses of families segregating autosomal recessively inherited neonatal diabetes, craniosynostosis and dominantly inherited renal dysplasia using the Affymetrix 10K SNP array. A single locus was identified for each disease state, two of which are novel. The performance of the SNP array, both in terms of efficiency and precision, indicates that such platforms will become the dominant technology for performing genomewide linkage searches.

Townes-Brocks syndrome (TBS) is an autosomal dominant malformation syndrome characterized by renal, anal, ear, and thumb anomalies caused by SALL1 mutations. To date, 36 SALL1 mutations have been described in TBS patients. All but three of those, namely p.R276X, p.S372X, and c.1404dupG, have been found only in single families thereby preventing phenotype-genotype correlations. Here we present 20 novel mutations (12 short deletions, five short duplications, three nonsense mutations) in 20 unrelated families. We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia. We show that 46 out of the now 56 SALL1 mutations are located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hotspot region to a stretch of 802 bp within exon 2. Of note, only two SALL1 mutations would result in truncated proteins without the glutamine-rich domain, one of which is reported here. The latter is associated with anal, ear, hand, and renal manifestations, indicating that the glutamine-rich domain is not required for typical TBS.

SummaryHermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles—melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally cloned the gene, and identified three pathologic mutations of the gene, in patients from Puerto Rico, Japan, and Europe. Here, we describe mutation analysis of 44 unrelated Puerto Rican and 24 unrelated non–Puerto Rican HPS patients. A 16-bp frameshift duplication, the result of an apparent founder effect, is nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. We also describe six novel HPS mutations: a 5′ splice-junction mutation of IVS5, three frameshifts, a nonsense mutation, and a one-codon in-frame deletion. These mutations define an apparent frameshift hot spot at codons 321–322. Overall, however, we detected mutations in the HPS gene in only about half of non–Puerto Rican patients, and we present evidence that suggests locus heterogeneity for HPS.