Dvorah Abeliovich

Prevalence and Evolutionary Origins of the del(GJB6-D13S1830) Mutation in the DFNB1 Locus in Hearing-Impaired Subjects: A Multicenter Study

Mutations in GJB2, the gene encoding connexin-26 at the DFNB1 locus on 13q12, are found in as many as 50% of subjects with autosomal recessive, nonsyndromic prelingual hearing impairment. However, genetic diagnosis is complicated by the fact that 10%-50% of affected subjects with GJB2 mutations carry only one mutant allele. Recently, a deletion truncating the GJB6 gene (encoding connexin-30), near GJB2 on 13q12, was shown to be the accompanying mutation in approximately 50% of these deaf GJB2 heterozygotes in a cohort of Spanish patients, thus becoming second only to 35delG at GJB2 as the most frequent mutation causing prelingual hearing impairment in Spain. Here, we present data from a multicenter study in nine countries that shows that the deletion is present in most of the screened populations, with higher frequencies in France, Spain, and Israel, where the percentages of unexplained GJB2 heterozygotes fell to 16.0%-20.9% after screening for the del(GJB6-D13S1830) mutation. Our results also suggest that additional mutations remain to be identified, either in DFNB1 or in other unlinked genes involved in epistatic interactions with GJB2. Analysis of haplotypes associated with the deletion revealed a founder effect in Ashkenazi Jews and also suggested a common founder for countries in Western Europe. These results have important implications for the diagnosis and counseling of families with DFNB1 deafness.

The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant?

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of serositis. To date more then 18 mutations responsible for the disease were identified in the MEFV gene, one such a mutation is E148Q in exon 2 of the gene. While screening FMF patients for mutations in the MEFV gene, we have identified 2 individuals parents of 2 unrelated FMF patients, who were homozygous for E148Q mutation. Upon clinical examination they were absolutely disease free and therefore raised the possibility that this mutation is a benign polymorphism rather than a mutation causing disease. To further investigate the role of the E148Q in FMF we analyzed 25 parents of FMF patients and a control group of 70 individuals, Jews of Moroccan extraction to match for ethnicity of the patients. The rate of E148Q in the control group was 6.4%, being 7.8% among the patient group. Among the parents group (obligatory carriers), in addition to the 2 parents that were homozygous E148Q, in 2 families one of the parents was heterozygote for E148Q but transmitted the other allele (apparently with unknown FMF mutation) to the affected child. Two healthy sibs of one of the E148Q homozygous were also homozygous E148Q. These observations are not in accordance to the notion that E148Q is a mutation causing disease. Hum Mutat 15:385–386, 2000.

The mechanisms involved in formation of deletions and duplications of 15q11-q13.

Haplotype analysis was undertaken in 20 cases of 15q11-q13 deletion associated with Prader-Willi syndrome (PWS) or Angelman syndrome (AS) to determine if these deletions arose through unequal meiotic crossing over between homologous chromosomes. Of these, six cases of PWS and three of AS were informative for markers on both sides of the deletion. For four of six cases of paternal 15q11-q13 deletion (PWS), markers on both sides of the deletion breakpoints were inferred to be of the same grandparental origin, implying an intrachromosomal origin of the deletion. Although the remaining two PWS cases showed evidence of crossing over between markers flanking the deletion, this was not more frequent than expected by chance given the genetic distance between proximal and distal markers. It is therefore possible that all PWS deletions were intrachromosomal in origin with the deletion event occurring after normal meiosis I recombination. Alternatively, both sister chromatid and homologous chromosome unequal exchange during meiosis may contribute to these deletions. In contrast, all three cases of maternal 15q11-q13 deletion (AS) were associated with crossing over between flanking markers, which suggests significantly more recombination than expected by chance (p = 0.002). Therefore, there appears to be more than one mechanism which may lead to PWS/AS deletions or the resolution of recombination intermediates may differ depending on the parental origin of the deletion. Furthermore, 13 of 15 cases of 15q11-q13 duplication, triplication, or inversion duplication had a distal duplication breakpoint which differed from the common distal deletion breakpoint. The presence of at least four distal breakpoint sites in duplications indicates that the mechanisms of rearrangement may be complex and multiple repeat sequences may be involved.

The H Syndrome Is Caused by Mutations in the Nucleoside Transporter hENT3

The H syndrome is a recently reported autosomal-recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, and fixed flexion contractures of the toe joints and the proximal interphalangeal joints. Homozygosity mapping in five consanguineous families resulted in the identification of mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3. Three mutations were found in 11 families of Arab and Bulgarian origin. The finding of several different mutations in a small geographic region implies that the H syndrome might be rather common. The identification of mutations in the SLC29A3 gene in patients with a mild clinical phenotype suggests that this is a largely underdiagnosed condition and strongly suggests that even oligosymptomatic individuals might have the disorder.

Contribution of connexin 26 mutations to nonsyndromic deafness in Ashkenazi patients and the variable phenotypic effect of the mutation 167delT

Twenty-seven unrelated Jewish Ashkenazi patients with nonsyndromic prelingual deafness (NSD) were analyzed for mutations in the coding sequence of the connexin 26 (Cx26) gene. Biallelic mutations were identified in 19 of the 27 patients (70.4%); 12 were homozygous for the mutation 167delT, 2 were homozygous for the mutation 35delG, and 5 were compound 167delT/35delG heterozygotes. In addition three patients were heterozygous with no second identified mutation in the Cx26 gene. Biallelic mutations in the Cx26 gene account for 83% of familial cases and 44% of the sporadic cases. Among 268 unselected Ashkenazi individuals, 20 were 167delT/N heterozygotes, giving an estimate of 7.5% carrier frequency. Based on the 167delT carrier frequency in three studies (including the present one), it is expected that 167delT/167delT homozygotes account for 70% of all patients with NSD (1 in 1300). The hearing capacity of 30 patients (probands and their sibs) with biallelic Cx26 mutations and at least one allele with 167delT demonstrated inter- and intrafamilial variability from profound to mild hearing impairment.

Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations

Background: The risks for cancers other than breast (BC) or ovarian (OC) cancer in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers were elevated in studies of carrier families. However, case–control studies did not confirm this observation. Objective: To compare the risks for other cancers in BRCA1/2 mutation carriers and non-carriers, all affected with BC and/or OC. Both groups share risk modifiers of BC/OC, which enabled assessment of the role of BRCA1/2 mutations. Methods: 1098 Ashkenazi Jewish women affected with BC and/or OC were ascertained during 1995–2003; molecular testing revealed 229 BRCA1 and 100 BRCA2 carriers and 769 non-carriers. COX proportional hazard models were used to evaluate the risk of other cancers. Analyses were conducted including all other cancers or only those diagnosed after BC/OC diagnosis. Results: The HRs for any other cancer were 2.6 (95% CI 1.7 to 4.2, p<0.001) and 1.8 (95% CI 0.95 to 3.6, p = 0.07) in BRCA1 and BRCA2 carriers, respectively. The corresponding colon cancer HRs were 3.9 (95% CI 1.3 to 12.1, p = 0.02) and 2.3 (95% CI 0.5 to 11.3, p = 0.3) in BRCA1 and BRCA2 carriers. The HR for lymphoma was 11.9 (95% CI 3.1 to 46.2, p = 0.001) in BRCA2 carriers. Risk estimates for other cancers after the onset of BC/OC were similar. Conclusion: A 2.5-fold increase in any other cancer and a fourfold risk of colon cancer were found among BRCA1 carriers. The corresponding HRs in BRCA2 carriers were non-significant, except for the markedly elevated risk of lymphoma. These results suggest a role for BRCA1/2 mutations in colorectal cancer risk in a subgroup of BC/OC-affected carriers.

Machado-Joseph disease: correlation between the clinical features, the CAG repeat length and homozygosity for the mutation.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder associated with the expansion of a CAG trinucleotide repeat in the MJD1 gene located on 14q32.1. We confirmed that the CAG expansion caused MJD in a Yemenite Jewish family and demonstrated that most of the clinical variation among members of this family was due to the genotype of the affected individuals. Six patients who presented with an early onset (25 years) and severe disorder were found to be homozygous for the CAG expansion. Among 5 heterozygotes for the CAG expansion older than 40 years, one had neurological symptoms from the age of 45, while the others were asymptomatic. In one of the heterozygotes, no neurological symptoms were present when last examined at the age of 66. Homozygosity for the MJD1 mutation was the main cause of variability in this large family, however, other factors clearly played a role in the expression of the gene. We could demonstrate that homozygote sibs with similar expansion in both alleles had significant differences in disease severity. Gender did not affect the clinical expression in this family.

Comparison of phenotype in uniparental disomy and deletion Prader-Willi syndrome: Sex specific differences

Prader-Willi syndrome (PWS) results primarily from either a paternal deletion of 15q11-q13 or maternal uniparental disomy (UPD) 15. Birth parameters and clinical presentation of 79 confirmed UPD cases and 43 deletion patients were compared in order to test whether any manifestations differ between the two groups. There were no major clinical differences between the two classes analyzed as a whole, other than the presence of hypopigmentation predominantly in the deletion group. However, there was a significant bias in sex-ratio (P < .001) limited to the UPD group with a predominance (68%) of males. An equal number of males and females was observed in the deletion group. When analyzed by sex, several significant differences between the UPD and deletion groups were observed. Female UPD patients were found to be less severely affected than female deletion patients in terms of length of gavage feeding and a later onset of hyperphagia. Although these traits are likely to be influenced by external factors, they may reflect a milder presentation of female UPD patients which could explain the observed sex bias by causing under-ascertainment of female UPD. Alternatively, there may be an effect of sex on either early trisomy 15 survival or the probability of somatic loss of a chromosome from a trisomic conceptus.

Sporadic phaeochromocytomas are rarely associated with germline mutations in the von Hippel-Lindau and RET genes.

von Hippel‐Lindau (VHL) disease and multiple endocrine neoplasia type 2 (MEN2) are autosomal dominant cancer syndromes. In both conditions, phaeochromocytoma is a prominent feature. It has recently been suggested that phaeochromocytoma can be the presenting and sole clinical manifestation of these multi–organ syndromes. The aim of this study was to ascertain the incidence of VHL and MEN2 among patients with sporadic phaeochromocytoma by mutational analysis.

A deletion/insertion mutation in the BRCA2 gene in a breast cancer family: A possible role of the Alu‐polyA tail in the evolution of the deletion

Patients with breast and/or ovarian cancer were screened for gross rearrangements in the BRCA2 gene by Southern hybridization, with exon 10 and a fragment of exon 11 used as probes. One breast cancer patient with a positive family history had a 6.2‐kb deletion including exons 12 and 13. The deletion breakpoint in intron 11 was in the 3′ polyA tail of an Alu element, where a track of ≈60 adenine nucleotide residues was inserted. Expansion of the Alu‐polyA tail may have resulted from polymerase slippage during replication, representing a novel mechanism in which Alu elements mediate deletion/insertion mutations.