Medico-genetical study of the Uzbekistan population. IX. Variability of hereditary pathology, territorial distribution of hereditary diseases and hereditary disease load in the population of the Urgut district of the Samarkand region

Medical-genetic study was carried out in the population of Samarkand province (the population size about 150 000). Hereditary pathology was ascertained among families with two or more affected members with chronic diseases. 110 families with 210 patients were registered. The most frequent were autosomal-recessive disorders (42 nozological forms). 15 nozological forms are probably "new" conditions in this province, because they were absent in our previous medical-genetic study of this province. A tendency to local accumulation of families with the same disorder in small populations was observed. The load of autosomal-recessive disorders comprised 2.2 X 10(-3) affected, that of autosomal-dominant disorders being 0.51 X 10(-3) and of X-linked disorders being 0.25 X 10(-3) males. The importance of assortative maitings in manifestation of rare autosomal-recessive genes in Uzbek population is discussed.     

Medico-genetic study of the population of Turkmenistan. I. Hereditary diseases in 5 districts of the Ashkabad region

Medico-genetic characteristics of the Ashkhabad province of Turkemenia are given. 23 nosological forms of hereditary diseases were found. The population load estimated per 1000 of autosomal-recessive (AR) diseases was 0.7, autosomal-dominant (AD) - 0.4, X-linked - 0.5. Inbreeding coefficient for the families with AR pathology was 0.03529, with AD - 0.01172. The study of territorial distribution of hereditary disease detected slightly marked local accumulation of certain forms of hereditary diseases.     

The Usher syndrome in the Lebanese population and further refinement of the USH2A candidate region

Usher syndrome (USH) is an autosomal-recessive disease characterized by neurosensory deafness and progressive retinitis pigmentosa. So far, three clinical types of Usher syndrome have been defined, and are caused by defects at more than eight loci. We report the linkage analysis of seven Lebanese families with Usher syndrome, two with type I (USH1) and five with type II (USH2). We demonstrate that one family is linked to the USH1C locus, a rare form of USH1 only reported in the French Acadian population. Linkage analysis of the five USH2 families with recently mapped loci allowed us to reduce the USH2A candidate region to a very small interval flanked by D1S2646/D1S2629 and D1S2827. Furthermore, haplotype comparison between the different families suggests a founder effect for the USH2A mutation among the different Lebanese ethnic groups, while a genetic heterogeneity is noted for Usher syndrome type I. Received: 9 January 1998 / Accepted: 23 March 1998     

Functional Null Mutations of MSRB3 Encoding Methionine Sulfoxide Reductase Are Associated with Human Deafness DFNB74

The DFNB74 locus for autosomal-recessive, nonsyndromic deafness segregating in three families was previously mapped to a 5.36 Mb interval on chromosome 12q14.2-q15. Subsequently, we ascertained five additional consanguineous families in which deafness segregated with markers at this locus and refined the critical interval to 2.31 Mb. We then sequenced the protein-coding exons of 18 genes in this interval. The affected individuals of six apparently unrelated families were homozygous for the same transversion (c.265T>G) in MSRB3, which encodes a zinc-containing methionine sulfoxide reductase B3. c.265T>G results in a substitution of glycine for cysteine (p.Cys89Gly), and this substitution cosegregates with deafness in the six DFNB74 families. This cysteine residue of MSRB3 is conserved in orthologs from yeast to humans and is involved in binding structural zinc. In vitro, p.Cys89Gly abolished zinc binding and MSRB3 enzymatic activity, indicating that p.Cys89Gly is a loss-of-function allele. The affected individuals in two other families were homozygous for a transition mutation (c.55T>C), which results in a nonsense mutation (p.Arg19X) in alternatively spliced exon 3, encoding a mitochondrial localization signal. This finding suggests that DFNB74 deafness is due to a mitochondrial dysfunction. In a cohort of 1,040 individuals (aged 53–67 years) of European ancestry, we found no association between 17 tagSNPs for MSRB3 and age-related hearing loss. Mouse Msrb3 is expressed widely. In the inner ear, it is found in the sensory epithelium of the organ of Corti and vestibular end organs as well as in cells of the spiral ganglion. Taken together, MSRB3-catalyzed reduction of methionine sulfoxides to methionine is essential for hearing.     

Attitudes of deaf adults toward genetic testing for hereditary deafness.

Recent advances within molecular genetics to identify the genes for deafness mean that it is now possible for genetic-counseling services to offer genetic testing for deafness to certain families. The purpose of this study is to document the attitudes of deaf adults toward genetic testing for deafness. A structured, self-completion questionnaire was given to delegates at an international conference on the "Deaf Nation," held at the University of Central Lancashire in 1997. The conference was aimed at well-educated people, with an emphasis on Deaf culture issues. Eighty-seven deaf delegates from the United Kingdom returned completed questionnaires. The questionnaire had been designed to quantitatively assess attitudes toward genetics, interest in prenatal diagnosis (PND) for deafness, and preference for having deaf or hearing children. The results from this study provide evidence of a predominantly negative attitude toward genetics and its impact on deaf people, in a population for whom genetic-counseling services are relevant. Fifty-five percent of the sample thought that genetic testing would do more harm than good, 46% thought that its potential use devalued deaf people, and 49% were concerned about new discoveries in genetics. When asked about testing in pregnancy, 16% of participants said that they would consider having PND, and, of these, 29% said that they would prefer to have deaf children. Geneticists need to appreciate that some deaf persons may prefer to have deaf children and may consider the use of genetic technology to achieve this. Any genetic-counseling service set up for families with deafness can only be effective and appropriate if clinicians and counselors take into consideration the beliefs and values of the deaf community at large.     

The contribution of the DFNB1 locus to neurosensory deafness in a Caucasian population.

Classical studies have demonstrated genetic heterogeneity for nonsyndromic autosomal recessive congenital neurosensory deafness, with at least six loci postulated. Linkage analysis in two consanguineous Tunisian kindreds has demonstrated that one such deafness locus, DFNB1, maps near chromosome 13 markers D13S175, D13S143, and D13S115. We tested these markers for cosegregation with deafness in 18 New Zealand and 1 Australian nonconsanguineous kindreds, each of which included at least two siblings with nonsyndromic presumed congenital sensorineural deafness and that had a pedigree structure consistent with autosomal recessive inheritance. When all families were combined, a peak two-point lod score of 2.547 (theta = .1) was obtained for D13S175, 0.780 (theta = .2) for D13S143, and 0.664 (theta = .3) for D13S115. While there was no statistically significant evidence for heterogeneity at any of the three loci tested, nine families showed cosegregation of marker haplotypes with deafness. These observations suggest that the DFNB1 locus may make an important contribution to autosomal recessive neurosensory deafness in a Caucasian population. In the nine cosegregating families, phenotypic variation was observed both within sibships (in four families), which indicates that variable expressivity characterizes some genotypes at the DFNB1 locus, and between generations (in two families), which suggests allelic heterogeneity.     

Mutations in PNKP Cause Recessive Ataxia with Oculomotor Apraxia Type 4

Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3′-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms.     

Mutational analysis in Lebanese patients with congenital adrenal hyperplasia due to a deficit in 21-hydroxylase

Molecular defects in the gene encoding steroid 21-hydroxylase (CYP21) result in impairment of adrenal steroid synthesis in patients affected with autosomal-recessive congenital adrenal hyperplasias (CAH). In this study, we report on the molecular screening of six point mutations, large deletions, gene conversion events and duplications in 25 unrelated Lebanese families affected by CAH due to steroid 21-hydroxylase. The methods used (PCR-digestion and southern blot) allowed the detection of 96% of the disease chromosomes. In classical forms, the most frequent mutation was the splice site mutation in intron 2 accounting for 39% of the disease alleles. Gene conversion events accounted for 14% of the alleles, but no large deletions were found. In nonclassical forms, the V281L mutation in exon 7 represent 86% of the tested alleles. Genotype-phenotype correlations were as expected: Delta 8nt, Q318X and gene conversion correspond to SW forms, whereas the intron 2 splice site mutation may give either SW or SV forms; the V281L mutation was responsible for nonclassical forms. The spectrum of mutations underlines the genetic diversity of the Lebanese population. No correlation could be drawn out between mutations and some specific religious communities, except for the Delta 8nt mutation, which is present only in the Christian Maronite group. Molecular study of the CYP21 gene might constitute a good support for clinicians, especially in consanguineous families, for whom we could provide genetic counselling.     

WNT10A Mutations Are a Frequent Cause of a Broad Spectrum of Ectodermal Dysplasias with Sex-Biased Manifestation Pattern in Heterozygotes

Odonto-onycho-dermal dysplasia (OODD), a rare autosomal-recessive inherited form of ectodermal dysplasia including severe oligodontia, nail dystrophy, palmoplantar hyperkeratosis, and hyperhidrosis, was recently shown to be caused by a homozygous nonsense WNT10A mutation in three consanguineous Lebanese families. Here, we report on 12 patients, from 11 unrelated families, with ectodermal dysplasia caused by five previously undescribed WNT10A mutations. In this study, we show that (1) WNT10A mutations cause not only OODD but also other forms of ectodermal dysplasia, reaching from apparently monosymptomatic severe oligodontia to Schöpf-Schulz-Passarge syndrome, which is so far considered a unique entity by the findings of numerous cysts along eyelid margins and the increased risk of benign and malignant skin tumors; (2) WNT10A mutations are a frequent cause of ectodermal dysplasia and were found in about 9% of an unselected patient cohort; (3) about half of the heterozygotes (53.8%) show a phenotype manifestation, including mainly tooth and nail anomalies, which was not reported before in OODD; and (4) heterozygotes show a sex-biased manifestation pattern, with a significantly higher proportion of tooth anomalies in males than in females, which may implicate gender-specific differences of WNT10A expression.     

Prevalence and molecular-genetic typing of nonsyndromal neurosensory deafness in the Chuvash Republic

Summarized genetic epidemiological characteristics of nonsyndromic sensorineural deafness in six raions of Chuvash Republic (Cheboksary, Kanash, Morgaushi, Tsivil'sk, Mariinski Posad, and Alatyr') are presented. A total of 264,419 individuals were examined. Forty-five families (60 affected individuals) with autosomal recessive (AR) and 8 families (18 affected individuals) with autosomal dominant (AD) nonsyndromic sensorineural deafness (NSSD) were identified. The load of AD and AR NSSD in the raions examined was estimated. A correlation between the distribution of AR NSSD and genetic drift was demonstrated. Furthermore, the load of AR NSSD was substantially higher in the regions with higher differentiation level. The Spearman's correlation coefficient value was 0.87. Typing of the 35delG mutation in the gene for connexion 26 was carried out in 34 patients from 26 families with AR NSSD. Comparative estimates of the NSSD prevalence in a number of Russian populations were performed.     

Heterogeneity in Waardenburg syndrome.

Heterogeneity of Waardenburg syndrome is demonstrated in a review of 1,285 patients from the literature and 34 previously unreported patients in five families in the Netherlands. The syndrome seems to consist of two genetically distinct entities that can be differentiated clinically: type I, Waardenburg syndrome with dystopia canthorum; and type II, Waardenburg syndrome without dystopia canthorum. Both types have an autosomal dominant mode of inheritance. The incidence of bilateral deafness in the two types of the syndrome was found in one-fourth with type I and about half of the patients with type II. This difference has important consequences for genetic counseling.     

Recurrence risks for near relatives of children with sensori-neural deafness

In a sample of children with sensori-neural deafness and no evidence of a syndrome, ototoxic exposure, or autosomal dominant or X-linked family history, seen in the Division of Medical Genetics of The Montreal Children's Hospital, the probability of a sibling being similarly affected was about 1 in 6, both in French-Canadian families and the remainder of the sample. The frequency of deafness of early onset was measured in the uncles and aunts of probands, and these figures were used to derive approximate recurrence risks for the offspring of probands (about 1 in 130, ignoring the possibility of autosomal dominant mutation) and for the offspring of the probands' unaffected sibs (about 1 in 250). A rough estimate of the number of autosomal recessive loci contributing to sensori-neural deafness is derived as 13.     

Frequency of the 35delG allele causing nonsyndromic recessive deafness in the Algerian patients

Deafness is a heterogeneous disorder showing different patterns of inheritance and involving a multitude of different genes. Mutations in the GJB2 gene encoding connexin 26 (Cx26) protein are a major cause for non-syndromic autosomal recessive and sporadic deafness. Among these mutations, the c.35delG deletion is the most common mutation for sensorineural deafness. One hundred sixteen persons from fifty-eight families were tested by the method based on the principle of PCR-mediated-site-directed mutagenesis (PSDM), followed by a Bsl1 digestion. Mutation c.35delG was diagnosed in sixteen families (11 homozygotes and 5 heterozygotes). The low allelic frequency (17.24%) and low ratio of individuals homozygous (13.8%) and heterozygous (6.9%) for the c.35delG mutation suggest that there are other mutations in the GJB2 gene or other genes responsible for deafness in the Algerian population. This study reports a significant association (P=0.003) between first cousin consanguinity and non-syndromic prelingual deafness.     

Linkage study of DFNB3 responsible for hearing loss in human

BACKGROUND:

Hearing disorders represent a significant health problem worldwide. Recessive inherited cases of the deafness are more prevalent in Pakistan due to consanguineous marriages. Deafness caused by DFNB3 is due to mutation in the gene MYO XVA and its prevalence among Pakistani population is about 5%.

MATERIALS AND METHODS:

Families with at least two or more individual affected with deafness were selected from different areas of District Okara of Pakistan. Six consanguineous families of different ethnic groups having deaf individuals were studied. All these families had three or more deaf individuals in either two or more sib ships. Family history was taken to minimize the chances of other abnormalities. Pedigrees drawn by using Cyrillic software (version 2.1) showed that all the marriages were consanguineous and the families have recessive mode of inheritance. Three STR markers were selected and amplified on all the samples of six families through PCR. The PCR products were then genotyped on non denaturing polyacrylamide gel electrophoresis (PAGE). Haplotypes were constructed to determine the pattern of inheritance and also to determine whether a family was linked or unlinked with known DFNB3 locus.

RESULTS:

One out of six families showed linkage to the DFNB3 while rest of the families remained unlinked. Carriers of deafness genes were identified and information was provided to the families on request.

CONCLUSION:

Knowledge about the genetic causes of deafness provide insight into the variable expression of genes involved in this hereditary problem and may allow the prediction and prevention of associated health problems.     

Homozygous Mutations in ADAMTS10 and ADAMTS17 Cause Lenticular Myopia, Ectopia Lentis, Glaucoma, Spherophakia, and Short Stature

Weill-Marchesani syndrome (WMS) is a well-characterized disorder in which patients develop eye and skeletal abnormalities. Autosomal-recessive and autosomal-dominant forms of WMS are caused by mutations in ADAMTS10 and FBN1 genes, respectively. Here we report on 13 patients from seven unrelated families from the Arabian Peninsula. These patients have a constellation of features that fall within the WMS spectrum and follow an autosomal-recessive mode of inheritance. Individuals who came from two families and met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10. Linkage analysis and direct sequencing of candidate genes in another two families and a sporadic case with phenotypes best described as WMS-like led to the identification of three homozygous mutations in the closely related ADAMTS17 gene. Our clinical and genetic findings suggest that ADAMTS17 plays a role in crystalline lens zonules and connective tissue formation and that mutations in ADAMTS17 are sufficient to produce some of the main features typically described in WMS.     

Medico-genetic study of the population of Uzbekistan. VII. Variability of hereditary pathology in 4 regions of Khorezm province

Medical-genetic study was carried out in the population of Khorezm province (population size above 200 000 persons). Hereditary pathology was ascertained among families having two or more members affected with chronic non-infectious diseases. 155 families with 348 members affected with hereditary diseases were registered. The most frequent were autosomal recessive diseases (55 nosological forms in 104 families with 271 affected), then followed the autosomal dominant conditions (10 nosological forms in 21 families with 53 affected). The less frequent was X-linked recessive pathology (6 forms in 12 families with 20 affected). The main part of cases of autosomal recessive pathology were found in separate families and were not observed during previous medical-genetic studies in Uzbekistan. Three autosomal recessive conditions are probably new forms of hereditary pathology. The important role of assortative matings in manifestation of rare autosomal recessive genes in Uzbek population is discussed.     

CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness

Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia.