Jan E. Dumon

Mutations in the connexin 26 gene (GJB2) among Ashkenazi jews with nonsyndromic recessive deafness

BACKGROUND Mutations in the GJB2 gene cause one form of nonsyndromic recessive deafness. Among Mediterranean Europeans, more than 80 percent of cases of nonsyndromic recessive deafness result from inheritance of the 30delG mutant allele of GJB2. We assessed the contribution of mutations in GJB2 to the prevalence of the condition among Ashkenazi Jews. METHODS We tested for mutations in GJB2 in DNA samples from three Ashkenazi Jewish families with nonsyndromic recessive deafness, from Ashkenazi Jewish persons seeking carrier testing for other conditions, and from members of other ethnic groups. The hearing of persons who were heterozygous for mutations in GJB2 was assessed by means of pure-tone audiometry, measurement of middle-ear immittance, and recording of otoacoustic emissions. RESULTS Two frame-shift mutations in GJB2, 167delT and 30delG, were observed in the families with nonsyndromic recessive deafness. In the Ashkenazi Jewish population the prevalence of heterozygosity for 167delT, which is rare in the general population, was 4.03 percent (95 percent confidence interval, 2.5 to 6.0 percent), and for 30delG the prevalence was 0.73 percent (95 percent confidence interval, 0.2 to 1.8 percent). Genetic-linkage analysis showed conservation of the haplotype for 167delT but the existence of several haplotypes for 30delG. Audiologic examination of carriers of the mutant alleles who had normal hearing revealed subtle differences in their otoacoustic emissions, suggesting that the expression of mutations in GJB2 may be semidominant. CONCLUSIONS The high frequency of carriers of mutations in GJB2 (4.76 percent) predicts a prevalence of 1 deaf person among 1765 people, which may account for the majority of cases of nonsyndromic recessive deafness in the Ashkenazi Jewish population. Conservation of the haplotype flanking the 167delT mutation suggests that this allele has a single origin, whereas the multiple haplotypes with the 30delG mutation suggest that this site is a hot spot for recurrent mutations.

ASSIGNMENT OF X-LINKED HYDROCEPHALUS TO XQ28 BY LINKAGE ANALYSIS

X-linked recessive hydrocephalus (HSAS) occurs at a frequency of approximately 1 per 30,000 male births and consists of hydrocephalus, stenosis of the aqueduct of Sylvius, mental retardation, spastic paraparesis, and clasped thumbs. Prenatal diagnosis of affected males by ultrasonographic detection of hydrocephalus is unreliable because hydrocephalus may be absent antenatally. Furthermore, carrier detection in females is not possible because they are asymptomatic. Using four families segregating HSAS, we performed linkage analysis with a panel of X-linked probes that detect restriction fragment length polymorphisms. We report here that HSAS, in all tested families, is closely linked to marker loci mapping in Xq28 (DXS52, lod = 6.52 at theta of 0.03; F8, lod = 4.32 at theta of 0.00; DXS15, lod = 3.40 at theta of 0.00). These data assign HSAS to the gene-dense chromosomal band Xq28 and allow for both prenatal diagnosis and carrier detection by linkage analysis.

Infantile metachromatic leukodystrophy. Confirmation of a prenatal diagnosis.

Abstract Infantile metachromatic leukodystrophy was diagnosed in utero by the absence of arylsulfatase A in cultured amniotic-fluid cells. The diagnosis was confirmed since enzyme activity was not demonstrable in cultured fetal skin fibroblasts, liver, or brain, and since characteristic histologic metachromatic deposits were present in kidney. Electron microscopy showed abnormal cytoplasmic membrane-bound inclusions, composed in part of stacked lamellar structures, in renal tubular cells and in Schwann and endoneurial cells of the sciatic nerve. Intrauterine diagnosis of metachromatic leukodystrophy is thus a potentially valuable method. (N Engl J Med 288:1365–1369, 1973)

Neonatal Marfan syndrome with congenital arachnodactyly, flexion contractures, and severe cardiac valve insufficiency.

We describe a male neonate with severe arachnodactyly, hypermobility of the fingers, flexion contractures of elbows, wrists, hips, and knees, micrognathia, crumpled ears, rockerbottom feet, loose redundant skin, and ocular abnormalities. Severe cardiac valve insufficiency and aortic dilatation resulted in cardiac failure and death 20 hours after birth. This case represents the severe end of the clinical spectrum of Marfan syndrome. As similar patients have been reported, they may represent a separate mutation.

Fragile X trait in a large kindred: transmission also through normal males.

In the pedigree reported here two apparently normal males may have transmitted the fragile X chromosome. Eighteen family members were examined cytogenetically. The fragile X was detected in a high percentage of cells from nine mentally retarded members of this family (six males and three females) and in one female obligate carrier. Four other obligate carriers showed no or only a few cells with the fragile X.

Application of fluorescence in situ hybridization for early prenatal diagnosis of partial trisomy 6p/monosomy 6q due to a familial pericentric inversion

Wauters JG, Bossuyt PJ, Roelen L, van Roy B, Dumon J. Application of fluorescence in situ hybridization for early prenatal diagnosis of partial trisomy 6p/monosomy 6q due to a familial pericentric inversion. Clin Genet 1993: 44: 262–269.

Limb-body wall complex: 4 new cases illustrating the importance of examining placenta and umbilical cord.

Limb-body wall complex (LBWC) is a rare, sporadic, congenital defect defined as a combination of at least two of three characteristics: 1. limb defects, 2. anterior body wall defects, and 3. exencephaly or encephalocoele with/without facial clefts. Three pathogenic mechanisms have been proposed: early amnion rupture, vascular disruption and embryonic dysgenesis. In this study we carried out the pathological evaluation of four fetuses with LBWC and their placentas. None of the cases had craniofacial defects. Three fetuses showed an abdominal wall defect with eventration of abdominal organs, cloacal exstrophy, absent external genitalia, abnormal internal genitalia, scoliosis and lower limb defects. One fetus showed failure of closure of both thoracic and abdominal walls with ectopia cordis, evisceration of left lung and abdominal organs, severe reduction defect of left arm, but normal colon, anus, bladder, genitalia and lower limbs. All cases had a short, malformed umbilical cord, incompletely covered by amnion. The umbilical vessels were embedded in an amniotic sheet which connected the skin margin of the anterior body wall defect to the placenta. These anomalies suggest an abnormal body stalk development as a pathogenic mechanism for LBWC. Prenatally, the abnormal fetoplacental attachment can be detected ultrasonographically by the end of the first gestational trimester. Postnatally, the examination of placenta, umbilical cord and membranes is crucial in confirming the diagnosis of LBWC.

Molecular cytogenetic analysis of XX males using Y-specific DNA sequences, including SRY

SummaryXX maleness is the most common condition in which testes develop in the absence of a cytogenetically detectable Y chromosome. Using molecular techniques, it is possible to detect Yp sequences in the majority of XX males. In this study, we could detect Y-specific sequences, including the sex-determining region of the Y chromosome (SRY), using fluorescence in situ hybridization. In 5 out of 6 previously unpublished XX males, SRY was translocated onto the terminal part of an X chromosome. This is the first report in which translocation of an SRY-bearing fragment to an X chromosome in XX males could be directly demonstrated.

Reciprocal translocation between the proximal regions of the long arms of chromosomes 13 and 15 resulting in unbalanced offspring: characterization by fluorescence in situ hybridization and DNA analysis

SummaryWe describe two female siblings with similar clinical features consisting of hydrocephalus, scaphocephaly, hypotonia, mongoloid eye slant, blepharophimosis, micrognathia, supernumerary mouth frenula and mental retardation. Routine cytogenetic studies in the elder patient did not reveal any abnormality, and initially it was assumed that the syndrome had an autosomal recessive inheritance. However, a slightly larger chromosome 13 was seen in routine G-banded metaphases of the mother and the youngest of the two siblings. A shorter chromosome 15 was detected in the mother only. High resolution banding showed that the abnormal chromosome 13 contained an extra G-positive band at 13q12. The short chromosome 15 in the mother appeared to have a deletion of band q12. Fluorescence in situ hybridization using DNA markers specific to chromosomes 13 and 15 unequivocally showed that the mother was a carrier of a balanced reciprocal translocation t(13;15)(q12;q13), whereas the youngest siblings karyotype was 46,XX,-13,+der(15)t(13;15)(q12;q13)mat, resulting in partial monosomy 13pter→q12 and partial trisomy 15pter→q13. The proband is thus trisomie for the critical region responsible for Prader-Willi syndrome and Angelman syndrome; this was confirmed by DNA analysis demonstrating one paternal and two maternal alleles from multiallelic marker loci mapping to 15q11-q13. This report illustrates the sensitivity and specificity offered by fluorescence in situ hybridization and its usefulness in the diagnosis and delineation of subtle chromosomal rearrangements.

Frequency of the phenylalanine deletion (ΔF508) in the CF gene of Belgian cystic fibrosis patients

Cloning and sequencing of the CF gene has identified a three‐base‐pair deletion (ΔF508) responsible for CF in the majority of CF patients (Kerem et al. 1989). We have used the polymerase chain reaction with oligonucleotide primers bridging the ΔF308 deletion to analyze the presence or absence of this mutation in the Belgian CF population. The ΔF306 mutation was present in 80% (57 on 71) of CF chromosomes from 36 unrelated Belgian CF families from the region of Antwerp. This mutation was associated with haplotype B for the KM.19–XV‐2c RFLPs as 93% (53 on 57) of the CF chromosomes with the Δ306 mutation carried haplotype B.