A somatic origin of homologous Robertsonian translocations and isochromosomes

One t(14q14q), three t(15q15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes. Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21). All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin. In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin. One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation. UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes. These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange

The acrocallosal syndrome in a Turkish boy.

A 6 month old Turkish boy with the acrocallosal syndrome is reported. The patient, born to consanguineous, healthy parents, presented with macrocephaly, a prominent forehead, hypertelorism, polydactyly of the fingers and toes, severe motor and mental retardation, hypotonia, and absence of the corpus callosum. The mode of inheritance is discussed and our case is compared with previously reported cases of the syndrome

Recessive omodysplasia: five new cases and review of the literature.

BACKGROUND: Autosomal recessive omodysplasia (MIM 258315) is a rare skeletal dysplasia characterized by severe congenital micromelia with shortening and distal tapering of the humeri and femora to give a club-like appearance. Fewer than 20 cases have been reported in the literature so far. OBJECTIVE: The purpose of this study was to more clearly describe the clinical and radiographic phenotypes and their changes with age. MATERIALS AND METHODS: Five new patients, including two sibs, with autosomal recessive omodysplasia are presented. RESULTS: Clinical features are rhizomelic dwarfism with limited extension of elbows and knees and a distinct face with a short nose, depressed nasal bridge, long philtrum, midline haemangiomas in infants and cryptorchidism in males. Radiological findings are distal hypoplasia of the short humerus and femur with characteristic radial dislocation and radioulnar diastasis. CONCLUSIONS: Based on a review of these and 16 previously reported patients, the regressive nature of the humerofemoral changes and the obvious male predominance are stressed. Phenotypic similarities with the atelosteogenesis group of disorders and with diastrophic dysplasia suggest common pathogenetic mechanisms

Maternal uniparental disomy 22 has no impact on the phenotype.

A 25-year-old normal healthy male was karyotyped because five of his wife's pregnancies terminated in spontaneous abortions at 6-14 wk of gestation. Cytogenetic investigation disclosed a de novo balanced Robertsonian t(22q;22q) translocation. Molecular studies revealed maternal only inheritance for chromosome 22 markers. Reduction to homozygosity for all informative markers indicates that the rearranged chromosome is an isochromosome derived from one of the maternal chromosomes 22. Except for the possibility of homozygosity for recessive mutations, maternal uniparental disomy 22 does not seem to have an adverse impact on the phenotype, apart from causing reproductive failure. It can be concluded that no maternally imprinted genes with major effect map to chromosome 22

Progressive autosomal dominant optic atrophy and sensorineural hearing loss in a Turkish family.

PURPOSE: To describe the clinical features, mode of inheritance, and linkage analysis of ten affected members of a three-generation family with progressive optic atrophy and progressive hearing loss. MATERIALS AND METHODS: The proband, a 10-year-old boy, presented with progressive visual failure. Ten other members in his family, including his mother, half-sister, aunt, two uncles, grandfather, and some of the cousins, also had progressive visual loss and hearing loss. Six affected and four unaffected cases were examined in detail. Blood samples were drawn from 16 members for DNA extraction. Two loci previously described for optic atrophy were tested for linkage in the present family. RESULTS: The mode of inheritance was clearly autosomal dominant. Six members of the family were found to have progressive optic atrophy and hearing loss, both starting in the first decade of life. Total or red-green color blindness was detected in some patients. None of the members of this family showed evidence of other systemic disorders; however, four had blepharochalasis. No other cause could be found for the hearing or the visual loss. Linkage analysis excluded OPA1 and OPA2. CONCLUSION: The present Turkish family belongs to the group of individuals with autosomal dominantly inherited optic atrophies with hearing loss. Linkage analysis excluded OPA1 and OPA2, indicating that a novel gene defect underlies the disease in this family. Further genome-wide linkage analysis and identification of the disease-associated gene will help define the pathophysiology of this syndrome

A Somatic Origin of Homologous Robertsonian Translocations and Isochromosomes

One t(14q14q), three t(15q15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes. Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21). All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin. In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin. One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation. UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes. These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange

Mutations in different components of FGF signaling in LADD syndrome.

Contains fulltext : 50020.pdf (publisher's version ) (Closed access)Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by lacrimal duct aplasia, malformed ears and deafness, small teeth and digital anomalies. We identified heterozygous mutations in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3) in LADD families, and in one further LADD family, we detected a mutation in the gene encoding fibroblast growth factor 10 (FGF10), a known FGFR ligand. These findings increase the spectrum of anomalies associated with abnormal FGF signaling