[Show abstract][Hide abstract] ABSTRACT: D15S63 is one of the loci, on chromosome 15q11-q13, that exhibit parent-of-origin dependent methylation and that is commonly used in the diagnosis of Prader-Willi or Angelman syndromes (PWS/AS). A 28-kb deletion spanning the D15S63 locus was identified in five unrelated patients; in each of them the deletion was inherited from a normal parent. Three of the five families segregating the deletion were reported to be of Jewish Ashkenazi ancestry, and in the other two families the ancestral origin was unknown. To determine whether the 28-kb deletion is a benign variant, we screened for the deletion in 137 unselected Ashkenazi individuals and in 268 patients who were referred for molecular diagnosis of PWS/AS, of whom 89 were Ashkenazi and 47 were of mixed origin (Ashkenazi and non-Ashkenazi Jews). In the control group, three individuals were carriers of the deletion; among the patients, three were carriers, all of whom were Ashkenazi Jews. There was no significant difference between the control group and the Ashkenazi patients, indicating that the deletion is not a cause of PWS- and AS-like syndromes. The frequency of the 28-kb deletion in the Ashkenazi population was 1/75. Since methylation analysis at the D15S63 locus may lead to misdiagnosis, we suggest the use of SNRPN, either in a PCR-based assay or as a probe in Southern hybridization, as the method of choice in the diagnosis of PWS/AS.
The American Journal of Human Genetics 02/2001; 68(1):261-3. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
American Journal of Medical Genetics 12/2000; 95(1):53-6.
[Show abstract][Hide abstract] ABSTRACT: 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.
Human Mutation 05/2000; 15(4):385-6. · 5.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Methylation analysis with probe PW71 (D15S63) is an established procedure to test patients suspected of having Prader-Willi syndrome or Angelman syndrome. Using this test, we have identified a 28-kb deletion spanning D15S63 in five independent families. Sequence analysis revealed identical breakpoints in all the families. The haplotype data are compatible with a common ancestral origin of the deletion in at least two families. The deletion was not found in 1, 000 unrelated controls. Although the deletion maps within the imprinting-center region, neither maternal nor paternal inheritance of the deletion appears to affect imprinting in proximal 15q. We conclude that the deletion is a rare neutral variant that can lead to false-positive results in the PW71-methylation test.
The American Journal of Human Genetics 01/2000; 65(6):1588-94. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutation analysis was performed on 42 unrelated Israeli Arab CF patients. The previously known mutations in this population, DF508, N1303K, G542X, 4010delTATT, and S549R(T>G), were identified in 57 CF alleles, leaving 28 CF alleles with unknown mutations. Screening of the coding sequence of the CFTR gene by a single strand conformation analysis (SSCA) and direct sequencing revealed three point mutations and two intragenic deletions, including 2183AA>G, R75X, S549R (A>C), 3120+1Kbdel8.6Kb and del(exon2). In the present sample of Israeli Arab patients, 12 mutations account for 92% of the CF alleles. The mutations DF508, N1303K, W1282X and 3120+1Kbdel8.6Kb were found in all Arab ethnic subgroups. The mutations G85E, R75X, 2183AA>G, and del(exon2) were confined to Muslim Arabs, and the mutations 4010delTATT, S549R(A>C) and G542X were confined to Christian Arabs. Hum Mutat 14:543, 1999.
Human Mutation 12/1999; 14(6):543. · 5.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Carriers of the mutations 185delAG and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene have a substantial life-time risk for breast and ovarian cancers (BC and OC). The aim of the study was to identify the clinical features and the hormonal risk modifiers in mutation carriers and the implication in suggested guidelines for treatment decisions in BRCA1/2 carrier patients.
Breast and/or ovarian cancer patients from the Oncology and Cancer Genetic clinics were tested for the three Ashkenazi founder mutations: 87 patients were identified as carriers of one of these mutations. Clinical presentation and age at onset were correlated with the mutations, in patients with bilateral BC or BC and OC, the length of time that elapsed between the diagnosis of the two cancers was recorded. We compared BC and OC patients with regard to ages at menarche, first pregnancy and menopause, number of pregnancies and deliveries, the use of oral contraceptives, hormonal replacement therapy and fertility treatments.
The carriers of the three BRCA1/2 Ashkenazi founder mutations did not differ in clinical presentation nor age at onset. Forty-three patients (74.1%) of 58 BC patients were diagnosed between the ages 30 and 50, only four (6.9%) patients were diagnosed after age 60. Of BC patients diagnosed before age 35, 63.6% developed second BC as compared to 25.5% of those diagnosed after age 35. Ovarian cancer was diagnosed after age 45 in 89.7% of the patients, only one patient was diagnosed under the age of 40. Oral contraceptives use was documented in 61.3% of BC patients as compared to 11.8% of OC patients. Other hormonal factors did not differ between the two groups.
The carriers of the three Ashkenazi founder mutations should be considered at the same risk for BC and for OC and treatment options should be the same. Mutation carriers diagnosed with BC before the age of 35 are at a very high risk for developing second breast cancer. Most ovarian cancers in carriers were diagnosed after age 45, and prophylactic oophorectomy should be postponed to the age of 45. Oral contraceptives might elevate the risk of BC in mutation carriers.
European Journal of Obstetrics & Gynecology and Reproductive Biology 08/1999; 85(1):75-80. · 1.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A deletion mutation of 8.6Kb in the CFTR gene, spanning the exons 17a, 17b and 18 was identified in 4 homozygous unrelated Palestinian CF patients. The patients were of various ethnic subgroups including Muslims, Christians and Druze. The deletion breakpoint occurred within an identical 4bp sequence in introns 16 and 18, and the mutation was defined as 3120+1Kbdel8.6Kb. A simple PCR based assay was designed and using this assay two compound heterozygote patients with the 3120+1Kbdel8.6Kb were identified. The 3120+1Kbdel8.6Kh hearing chromosomes had a common intragenic haplotype and variable flanking polymorphic markers, indicating that it is an ancient founder mutation.
Human Mutation 02/1999; 13(4):337. · 5.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are caused by the loss of function of imprinted genes in proximal 15q. In approximately 2%-4% of patients, this loss of function is due to an imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprinting center (IC). Here we describe the molecular analysis of 13 PWS patients and 17 AS patients who have an imprinting defect but no IC deletion. Heteroduplex and partial sequence analysis did not reveal any point mutations of the known IC elements, either. Interestingly, all of these patients represent sporadic cases, and some share the paternal (PWS) or the maternal (AS) 15q11-q13 haplotype with an unaffected sib. In each of five PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and four cases described elsewhere, the maternally imprinted paternal chromosome region was inherited from the paternal grandmother. This suggests that the grandmaternal imprint was not erased in the father's germ line. In seven informative AS patients reported here and in three previously reported patients, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding is not compatible with an imprint-switch failure, but it suggests that a paternal imprint developed either in the maternal germ line or postzygotically. We conclude (1) that the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error, (2) that these cases have a low recurrence risk, and (3) that the paternal imprint may be the default imprint.
The American Journal of Human Genetics 08/1998; 63(1):170-80. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Twenty-seven unrelated patients with biochemically and/or anatomically proven sporadic phaeochromocytoma were evaluated.
Constitutional DNA obtained from the patients was analysed by single stranded conformational analysis (SSCP) for mutations within the VHL gene coding sequence and by denaturing gradient gel electrophoresis (DGGE) for predominant mutations in exons 10, 11 and 16 of the RET proto-oncogene. The incidence of patients positive for either VHL or RET germline mutations was assessed.
Twenty-six of 27 patients had normal SSCP patterns in all three VHL gene exon segments and only one patient, with an atypical clinical presentation, had an aberrant pattern in exon 3 which upon DNA sequencing was shown to harbor a G to A transversion mutation at nucleotide 695. All patients had normal RET exon 10, 11 and 16 DGGE migration patterns.
Most, if not all, patients with typical unilateral sporadic phaeochromocytoma do not have von Hippel-Lindau disease or MEN2. Thus, clinical and/or molecular investigation for von Hippel-Lindau disease and MEN2 in this patient population does not appear to be indicated.
[Show abstract][Hide abstract] ABSTRACT: The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer. Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/or ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation. Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations.
The American Journal of Human Genetics 04/1997; 60(3):505-14. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer. Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/or ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation. Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations. 25 refs., 3 figs., 6 tabs.
The American Journal of Human Genetics 03/1997; 60(3). · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a pregnancy that was monitored due to increased risk for Down syndrome in the triple test, a normal karyotype was found in amniocentesis. Follow-up by serial ultrasound examinations revealed intrauterine growth retardation (IUGR) at 20 weeks of gestation. The parents decided to terminate the pregnancy and the karyotype of the placental fibroblasts was 47,XX,+2. Analysis of polymorphic markers of chromosome 2 demonstrated (a) that trisomy 2 was confined to the placenta (CPM), (b) that the trisomy 2 cell line was a result of a meiotic I error of paternal origin, and (c) that the fetal tissues with a normal karyotype were biparental disomy 2.
[Show abstract][Hide abstract] ABSTRACT: An association between the rare condition of transient neonatal diabetes mellitus and either uniparental disomy for chromosome 6 or dup(6)(q22q23) raised the assumption that in this location on chromosome 6 there is an imprinted gene. We diagnosed diabetes that developed in a baby girl immediately after birth and resolved after 7 weeks of insulin treatment. Due to some minor dysmorphic features, we investigated her karyotype and identified invdup(6)(q22q23). The duplication spans at least 10 cM including the DNA sites DS270,S314,S1684 and S310. This case further supports the assumption that an imprinted gene exists on chromosome 6q22-23.
European Journal of HumanGenetics 01/1997; 5(6):417-9. · 4.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Two sibs, carriers of unbalanced products of the translocation t(15;21)(q15;q22.1) pat, are described. The sister had Prader-Willi syndrome due to deletion 15 (pter > q15) and partial trisomy 21 (pter > q22.1); her brother had partial trisomy 15 (pter > q15) and partial monosomy 21 (pter > q22.1). The translocation breakpoint on chromosome 21 was located proximal to the SOD1 gene, within a region of 4.0 cM (2.3 Mb) between the loci D21S217 and D21S213. The correlations between the clinical presentation and the molecular findings of the two sibs are discussed in relation to other patients with partial trisomy and monosomy 21.
American Journal of Medical Genetics 12/1996; 66(1):45-51.
[Show abstract][Hide abstract] ABSTRACT: 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.
American Journal of Medical Genetics 11/1996; 65(2):133-6.