Annales de Génétique最新文献

We investigated 21 affected individuals in two unrelated monilethrix families of Indian origin and identified point mutation (g.4624G>A) in the HTM motif (exon-7) of the KRTHB6 gene in all the affected members leading to E413K change in this basic keratin. The HTM motif of KRTHB1, however, showed previously unreported two allelic variants, one with three novel variations (SNPs) in cis: g.4421insT (intronic); g.4461T>C (exonic); g.4485A>G (exonic) and second with only intronic variation (SNP) (g.4421insT). Interestingly, the two distinct phenotypes of: localized severe hair defect with beaded appearance confined to the scalp of all the affected members of Family 1 and of generalized unbeaded hair defect of moderate severity in Family 2, segregated in the two families, respectively, correlating with the two separate genotypes for the functionally critical HTM region of KRTHB1 gene in the background of E413K mutation in the KRTHB6 gene. Presence of E413K mutation in the HTM of KRTHB6 gene was not observed in the background of the allelic variant with three SNPs in KRTHB1 gene in homozygous condition in all the affected members of Family 1, affected with a localized but severe form of the disease. However, the same (E413K) mutation existed in the KRTHB6 gene in the background of the allelic variant with three SNPs in the KRTHB1 gene in homozygous condition, consistently in all the affected members of Family 2, where all its affected members showed the segregation of a milder form of the disease. Presence of both E413K mutation in the KRTHB6 and the variations in the KRTHB1 genes were not observed together in randomly selected 150 unaffected controls outside the two affected families. This is also the first report of HTM mutation of KRTHB6 gene in monilethrix cases of Indian origin and the first report of SNPs in the KRTHB1 gene in literature to our knowledge.

The occurrence of double aneuploidy in the same individual is a relatively rare phenomenon. We describe twin newborns with typical clinical features of Down’s syndrome, of which one revealed 48,XXY,+21 GTG-band karyotype. The second newborn died 2 days after its birth, and was clinically diagnosed having Down syndrome. Due to the same clinical features of the twins, the common placenta and amniotic sac, we speculate that they were monozygotics and as a result the second newborn should also be a Klinefelter. The purpose of this report is to present a rare case of possible coincidence of double aneuploidy in newborn twins. A review of the literature showed that double trisomy (48,XXY,+21) in a twin newborn infant has never occurred.

Gerstmann–Sträussler–Scheinker disease (GSS) is an adult onset, rare, genetically determined autosomal dominant prion disease. Clinically, it is characterized predominantly by slowly progressive spino-cerebellar dysfunction with ataxia, absent reflexes in the legs and cognitive impairment. Onset is usually in the fifth decade and in the early phase, ataxia is predominant. Mutations in the prion protein gene (PRNP) had been identified and the most important of these is at codon 129. A genotype–phenotype relationship with genetic polymorphism at residue 129 between methionine and valine has been supposed. We describe a patient with GSS and P102L–V129 mutation in which the onset with prominent psychiatric features characterized by apathy and depression and not with cerebellar sign and the clinical course with seizures, nor observed in P102L–V129 cases, allow us to confirm observations that the GSS caused by the 102 mutation is influenced by the codon 129 polymorphism with a specific genotype–phenotype influence, but probably other additional factors might be considered as background for phenotypic variability.

Interstitial deletion of the proximal short arm of chromosome 4, extending from p14 to p16.1 region, results in a distinct clinical syndrome. This proximal 4p deletion syndrome is characterized by variable degrees of mental retardation, unusual facies and minor dysmorphic features. Majority of the patients also show a tall, ectomorphic habitus and normal to excessive linear growth with age. While there have been several cases of such interstitial del(4p) cases reported, familial transmission of this condition has not been documented in the literature. This is the first report of a familial transmission of proximal del(4p) from a mother to her daughter, with both patients showing similar features. This report of the familial transmission of del(4p) has wider implications in genetic counseling.

Objective. – To delineate the phenotypic spectrum (clinical and gonadal features) from patients with a 45,X/46,X,mar(Y) karyotype based upon of their clinical, histological, cytogenetic and molecular evaluation.

Subjects. – Three patients with a 45,X/46,X,mar(Y) karyotype.

Methods. – Clinical assessment, karyotyping, endocrine evaluation, FISH and PCR analyses of several Y-chromosome loci and direct sequencing of the SRY gene.

Results. – The patients, two males and one female had varying degrees of impairment of sexual differentiation, with or without testis formation. One patient (reared as female and aged 17 years) had Turner syndrome with bilateral streak gonads. The second patient (2.4 years old) had ambiguous genitalia and presented a dysgenetic testis with a contralateral streak gonad. A third patient (26 years old) had bilateral dysgenetic testes (dysgenetic male pseudohermaphroditism). The ratio of 45,X vs. 46,X,+mar(Y) cells differed between patients and between different tissues. In each case the marker sexual chromosome was identified as a rearranged Y-chromosome (idic(Y)) using FISH and PCR analyses. In all cases the SRY gene was present in all tissues studied. No mutations were identified in this gene in any of the patients.

Conclusions. – The extent of male or female differentiation in these patients depends in part on the prevalence, time occurrence, and distribution of the 45,X cell line.

Maternal treatment with diethylstilbestrol (DES) during pregnancy can produce vaginal adenocarcinoma and other abnormalities of the vagina in her daughters when they reach adolescence or adulthood, miscarriages and absence of full term infants. Concerning malformations in newborns whose mothers were treated with DES, clitoromegaly and malformations of the uterus were reported in females and genital lesions in males. However, the frequencies of major congenital anomalies were not greater than expected. We report three cases of limb reduction defects (LRD) in the first generation of children whose mothers were treated with DES during pregnancy, and two children (one male, one female) with deafness in the second generation after intrauterine exposure to DES. The LRD were not associated with other congenital anomalies. The malformed children with LRD were born between 1965 and 1973. The deafness was also isolated. The two mothers who have no hearing problems and who are healthy were exposed in utero to DES in 1963 and 1965, respectively. Their children were born in 1989 and 1994, respectively. In conclusion, the association of LRD and hearing loss with intrauterine exposure to DES could be coincidental. However, some hypothesis may explain these associations. Congenital hearing loss in the second generation may suggest a transgenerational effect.

Two 48,XXYY males, a young and an adult patient, have been clinically and molecularly analysed. Clinical findings seem less severe in the young patient. This clinical difference could be mainly due to the age of the younger patient or, alternatively, the different pattern of X-inactivation observed in the two patients could play a role in the degree of the clinical manifestations.

We report the case of a female child presented at birth with hypotonia, growth retardation and respiratory distress. Chromosome study from peripheral blood showed a 46,XX,del(5)(p14pter) karyotype. Parental chromosome studies revealed that the mother carried an apparently balanced paracentric inversion of long arms of one chromosome 5, giving the karyotype 46,XX,inv(5)(q12q32), whereas paternal karyotype was normal. The maternal abnormality was confirmed by fluorescence in situ hybridization (FISH) and was not present in the daughter’s metaphases. Microsatellite analysis in the proposita and her parents permitted us to conclude that the deleted chromosome 5 was paternal in origin, as usually described. Therefore, as might have been expected, maternal paracentric inversion of chromosome 5q and “cri-du-chat syndrome” presented by the daughter were not related.

We describe a 7-month-old male child with Silver–Russel syndrome (SRS) phenotype, presented with two major clinical features: low birth weight, short stature, and minor features, such as macrocephaly, clinodactyly, essential for the diagnosis of SRS. Routine cytogenetic studies with GTG-banding showed 46,XY,t(11;16)(p13;q24.3). Fluorescence in situ hybridisation (FISH) with single copy probes BAC (11p13) and PAC (16q24.3), showed a reciprocal translocation. Chromosomal analysis of the mother was normal and the phenotypically normal father had apparently identical translocation t(11;16)(p13;q24.3). The disruption of growth factor genes at 11p and 16q breakpoint regions due to reciprocal translocation in the father might have caused SRS phenotype in the child.