Localization of the Gene for Sclerosteosis to the van Buchem Disease–Gene Region on Chromosome 17q12–q21

SummarySclerosteosis is an uncommon, autosomal recessive, progressive, sclerosing, bone dysplasia characterized by generalized osteosclerosis and hyperostosis of the skeleton, affecting mainly the skull and mandible. In most patients this causes facial paralysis and hearing loss. Other features are gigantism and hand abnormalities. In the present study, linkage analysis in two consanguineous families with sclerosteosis resulted in the assignment of the sclerosteosis gene to chromosome 17q12-q21. This region was analyzed because of the recent assignment to this chromosomal region of the gene causing van Buchem disease, a rare autosomal recessive condition with a hyperostosis similar to sclerosteosis. Because of the clinical similarities between sclerosteosis and van Buchem disease, it has previously been suggested that both conditions might be caused by mutations in the same gene. Our study now provides genetic evidence for this hypothesis

Legius Syndrome in Fourteen Families

Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome. © 2010 Wiley-Liss, Inc

Waardenburg Syndrome: Clinical Differentiation Between Types I and II

Here we present the results of a study performed on 59 patients affected by Waardenburg syndrome (WS), 30 with the I variant, 21 having the type II, and 8 of them being isolated cases without telecanthus. These patients belong to 37 families; the main contributions and conclusions are based on the detailed study of 25 of these families, examined using standard procedures. All patients were examined as to the presence of eight cardinal signs important for the diagnosis of the condition; from each patient, from many of his/her normal relatives, and from a control sample of 300 normal individuals stratified by age and sex, 23 different craniofacial measurements were obtained. We also estimated, using our own data as well those collected from the literature, the frequencies of the cardinal signs, based on a total sample of 461 affected individuals with WSI and 121 with WSII. In order to originate discriminant functions to separate individuals affected by one of the two variants, both metric (from craniofacial measurements) as well as categoric data (based on the frequencies of the cardinal signs or symptoms) were used. Discriminant analysis based on the frequency of the eight cardinal signs can improve the separation of WSI patients without telecanthus from those presenting the variant II. We present also a Table with the conditional probabilities favoring the diagnosis of WSI for suspect subjects without telecanthus and any combination of the other seven signs/symptoms. The discriminant function based on the four ocular measurements (inner and outer intercanthal, interpupillary, and inferior lacrymal distances), on the other side, perfectly classifies patients affected by one of the variants of WS, the same taking place when the average values of the W index of all affected individuals per family are used. The discriminant function based solely in the individual W index values of patients correctly classifies 93% of WSII subjects, but only 60% of the patients with the I variant of WS. ß 2003 Wiley-Liss, Inc. KEY WORDS: Waardenburg syndrome; genetic heterogeneity; discriminant analysis INTRODUCTION The Waardenburg syndrome (WS), first comprehensively described in 1951, is a genetically heterogeneous condition, each of its forms having a wide clinical spectrum with a very high degree of phenotypic expressivity. In the present paper, we will consider only the two most frequent variants (WSI and WSII) out of the four described so far. These two forms, together accounting for a prevalence of 2 to 3 affected individuals/100,000 in the general population, are determined by non-allelic autosomal dominant mutant genes with a high penetrance. WS is characterized clinically by the association of craniofacial dysmorphim, pigmentation defects, and severe sensorineural congenital hearing impairment. The craniofacial dysmorphisms most commonly seen in affected individuals include telecanthus (in WSI only), broad and high nasal root, hypoplasia of the alae nasi, lower lacrimal dystopia, and synophrys. Telecanthus (dystopia canthorum lateroversa) is classically described as an increase of inner ocular intercantal distance (IID) with preservation of both interpupillary (IPD) and outer intercantal (OID) distances. WS patients with this sign, however, commonly present larger values of the other two measurements, so that they exhibit a certain degree of hypertelorism. Patients frequently display conspicuous pigmentary defects of the irides (totally or partially heterochromic and bright hypochromic blue irides), hypopigmented skin spots, and partial hair albinism (white forelock or early graying). The first variant (WSI), with telecanthus, is caused by mutations at the PAX3 gene located in 2q35, while the second (WSII) is determined by other non-allelic autosomal dominant mutations located in the region 3p12.3 ! 3p14.1 of the MITF gene. Many of these are point mutations involving single-base substitutions and the number of different mutations described so far for both loci is so large that the molecular screening for them in WS can not be routinely performed in most laboratories. Because of all this, the differential diagnosis between variants I and II still relies largely on classic clinical methods. Clinical signs and symptoms are similar in both conditions, but telecanthus is known to occur only in WSI; the other characteristics have contrasting frequencies in both forms, especially iris and hair pigmentary disturbances and deafness. The penetrance of the last trait is higher in the second variant of WS, which has therefore a poorer clinical prognosis. Telecanthus (sometimes hypertelorism) is the most important sign for the differentiation between both forms, because it is present in the vast majority (95-99%) of WSI patients and virtually absent in those with the WSII variant. The presence of conspicuous craniofacial dysmorphisms in WS explains why the condition has been widely studied anthropometrically. The first of these studies was performed on Waardenburg's original data by Since the penetrance of the telecanthus trait and consequently the efficiency of the W index-although generally high-are both incomplete In this paper, we describe 59 individuals affected by the Waardenburg syndromes WSI and WSII, belonging to 25 Brazilian families. A detailed craniofacial phenotypic description of all affected individuals is presented, as well as the values of several measurements taken in these patients. The relative frequencies of cardinal signs and the values of craniofacial measurements are used to compare, through discriminant analysis, WSI and WSII affected individuals. MATERIALS AND METHODS Out of the 25 families studied personally, 18 were ascertained in the Laboratory of Human Genetics (LGH, Departamento de Biologia, IB USP, São Paulo) and seven were examined at the Hospital de Reabilitação de Anomalias Cranio-Faciais (HRAC, Faculdade de Odontologia, USP, Bauru). For this, we used a standardized routine for physical examination that included the investigation, in all affected individuals (with the exception of a few instances in which one measurement could not be recorded and the corresponding feature could not be evaluated objectively), of the following eight cardinal signs and symptoms of WS: telecanthus, synophrys, iris pigmentation disturbances, localized albinism on hair (white forelock and early graying), hearing impairment, nasal root hyperplasia, hypopigmented skin spots, and lower lacrimal dystopia. We selected also, through review of the international literature, 44 different papers published from 1951 to 1995 with complete clinical presentation of cases of WS Waardenburg Syndrome 225 non-mentioned characteristic was absent, the estimate for its frequency is given by under the hypothesis (b) that the non-mentioned sign/ symptom was not investigated, its frequency estimate is given by x 00 ¼ X/(X þ Y) ¼ X/(N À Z), with expected binomial variance var(x 00 ) ¼ x 00 (1 À x 00 )/(N À Z). Obviously, the true estimate of the frequency is given by an unknown quantity within an interval with lower und upper limits given by x 0 and x 00 . If there is no additional information enabling us to choose one out of the two hypotheses above, an estimate of the true frequency x can be obtained by weighing the estimates x 0 and x 00 by the reciprocal of their expected binomial variances. This estimate will be used throughout this work to contrast the frequencies of the cardinal signs in a sample of WSI and WSII patients combining our data with those from the literature. We also determined-in random samples of Caucasian individuals stratified by sex and age (total of 300 individuals) and in affected individuals and in their relatives belonging to ten of our 25 families-23 different craniofacial measurements of interest in the diagnosis of WS. Some of these measurements were used for comparing controls and patients as well as types I and II of WS. 226 Pardono et al. We have classified as WSI all the patients, familial or isolated, that presented conspicuous telecanthus. In order to classify as WSI a case of WS without telecanthus, this affected individual should always belong to a family with at least one typical case of WSI (with telecanthus). Therefore, all cases of WSI without telecanthus presented here are familial, whereas all isolated cases of WS classified as WSI present with the sign. Inversely, all cases of WS classified as WSII are necessarily familial, that is, they belong strictly to families with at least one more affected individual, none of them presenting telecanthus. In the cases selected from literature, we applied the same classification criteria, systematically disregarding the classification of isolated cases of WS without telecanthus as being WSII. In the presentation of our cases in the Results and Discussion section, all isolated WS patients without telecanthus were grouped in a group labelled as WSII?, but their data were not used in the statistical analyses described below. For the study of cardinal characteristics, the application of the above-mentioned stringent criteria to the cases from literature enabled us to consider a total of 461 WSI patients (29 of them not presenting telecanthus) and 121 carriers of the WSII variant. With the addition of our own data to those from the literature, the discriminant analysis performed with categorical data was based, therefore, on totals of 491 WSI and 142 WSII patients, respectively. The techniques of statistical analysis used throughout this paper are detailed in standard textbooks (e.g., Zar [1999]). Those on linear and non-linear discriminant analysis in particular are detailed in Smith [1947, 1969], Penrose [1947], and Karn and Penrose [1951]. RESULTS AND DISCUSSION Description of Cases Using a modification of the genealogy symbols proposed by Discriminant Analysis Using the Frequencies of Cardinal Signs and Symptoms The estimated frequencies of the eight cardinal characteristics of WS were calculated from reliable case descriptions in the literature and are shown in Waardenburg Syndrome 227 Comparing the observed frequencies of each sign in the groups of WSI and WSII patients through chisquared tests in 2 Â 2 contingency tables, we obtained in all cases test figures that were significant at least at the 1% level. The elements necessary for performing a simplified categoric discriminant analysis, together with an application example, are summarized in Since there are only seven other possible signs besides telecanthus, all the possible combinations of these seven signs/symptoms (presence or absence) reduce to 2 7 ¼ 128. 38 out of these 128 combinations generate probability figures larger than 95% or less than 5% favoring the diagnosis of WSI and are shown in We could obtain, combining our data with those from the literature, complete individual phenotypic descriptions of 111 patients affected by WSII out of the 142 used for deriving the probabilities shown in Discriminant Analysis Based on Craniofacial Measurements First we compared the craniofacial measurements between WSI and WSII patients, and between WS patients and controls through t tests with allowance for variance heterogeneity. Using as selection criterion all variables that were statistically different between any of the two comparison groups at least at the 0.001 significance level, we chose the following variables to be used on discriminant analysis: inner intercanthal distance (IID); outer intercanthal distance (OID); interpupillary distance (IPD); lower interlacrimal distance (LID); nose interalar distance (IAD); mean length of ear (EML), obtained by averaging the longitudinal length of both auricles; and the W index (WI), a composite measure used in the literature for separating WSI and WSII patients and described in the introduction section. We decided to also include the variables facial length or morphological face height (MFH) and the mean width of ear (EMW), a measurement obtained by averaging the transversal length of both auricles. These two measurements, in spite of not showing statistical significance at the 0.001 level, exhibited differences at a critical level much less than 0.01. The statistical parameters of these nine measurements, estimated in the groups of WSI and WSII patients and controls, are shown i

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network

Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Purpose RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. Methods Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. Results Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. Conclusion This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases