Detection of a novel unbalanced X;21 translocation in a girl with Turner syndrome phenotype.

OBJECTIVE: To describe a novel unbalanced X;21 translocation resulting in a derivative pseudodicentric chromosome X;21 lacking the critical region for ovarian development and function, in a 16-year-old girl referred for cytogenetic analysis due to primary amenorrhea and Turner-like features. METHODS: Cytogenetic analysis of the proband and her parents was performed on peripheral blood lymphocytes by GTG banding. Molecular cytogenetic FISH analysis was performed on metaphase preparations, using X chromosome centromeric probe and telomeric and pancentromeric peptide nucleic acid (PNA) analog probes. The HUMARA assay as well as methylation studies for PCSK1N and FMR-1 loci were performed. RESULTS: Cytogenetic analysis revealed a de novo unbalanced X;21 translocation, described as 45,X,der(X)t(X;21)(q22.2;p11.2),-21. FISH analysis showed that the derivative X chromosome carried both the X and 21 centromeres, as well as, the Xp and 21q telomeres. The karyotype was thus reevaluated as 45,X,psu dic(21;X)(21qter→21p13::Xq22.2→Xpter),-21. X inactivation studies revealed that the derivative chromosome was of paternal origin and confirmed the selective inactivation of the derivative X segment of the pseudodicentric chromosome. CONCLUSIONS: Primary amenorrhea and other Turner-like characteristics of the proband are apparently due to the loss of the Xq22.2→Xqter critical region which contains critical genes for the ovarian development and function. The chromosome X segment of the derivative pseudodicentric chromosome is selectively inactivated, but inactivation does not seem to spread onto the translocated chromosome 21, accounting probably for the lack of severe clinical consequences which would result from monosomy 21.

Bone Marrow Failure in Fanconi Anemia: Clinical and Genetic Spectrum in a Cohort of 20 Pediatric Patients.

Prognostic refinement in Fanconi anemia (FA) is needed, especially when considering allogeneic hematopoietic stem cell transplantation (HCT). We studied 20 children with FA and bone marrow failure from a single center. According to Hôpital Saint-Louis risk classification for FA, patients were classified in stage A (no or mild cytopenia/dysplasia), B (single non-high-risk cytogenetic abnormality), C (severe cytopenia and/or significant dysplasia and/or high-risk cytogenetic abnormality), and D (myelodysplastic syndrome with excess of blasts/acute myeloid leukemia) in 4, 2, 13, and 0 cases, respectively. Nine patients received androgens +/- steroids, with a response rate of 30%, and 11 patients underwent HCT. Ten-year cumulative incidence (CI) of myelodysplastic syndrome/acute myeloid leukemia and overall survival (OS) were 21.9% and 45.3%, respectively, in the entire cohort, whereas cumulative incidence of transplantation-related mortality and OS were 27% and 63%, respectively, in patients who underwent HCT. Patients with significant dysplasia at diagnosis (stages C and D) had significantly shorter OS post-HCT as compared with patients without dysplasia. All patients in stages C and D at diagnosis or during evolution died from their disease. HCT in recent years was associated with more favorable outcomes. Larger cohorts could validate homogenous reporting of risk and help decision-making, particularly for HCT.

Application of high-resolution array comparative genomic hybridization in children with unknown syndromic microcephaly.

BackroundMicrocephaly can either be isolated or it may coexist with other neurological entities and/or multiple congenital anomalies, known as syndromic microcephaly. Although many syndromic cases can be classified based on the characteristic phenotype, some others remain uncertain and require further investigation. The present study describes the application of array-comparative genomic hybridization (array-CGH) as a diagnostic tool for the study of patients with clinically unknown syndromic microcephaly.MethodsFrom a cohort of 210 unrelated patients referred with syndromic microcephaly, we applied array-CGH analysis in 53 undiagnosed cases. In all the 53 cases except one, previous standard karyotype was negative. High-resolution 4 × 180K and 1 × 244K Agilent arrays were used in this study.ResultsIn 25 out of the 53 patients with microcephaly among other phenotypic anomalies, array-CGH revealed copy number variations (CNVs) ranging in size between 15 kb and 31.6 Mb. The identified CNVs were definitely causal for microcephaly in 11/53, probably causal in 7/53, and not causal for microcephaly in 7/53 patients. Genes potentially contributing to brain deficit were revealed in 16/53 patients.ConclusionsArray-CGH contributes to the elucidation of undefined syndromic microcephalic cases by permitting the discovery of novel microdeletions and/or microduplications. It also allows a more precise genotype-phenotype correlation by the accurate definition of the breakpoints in the deleted/duplicated regions.

Erratum to: An interstitial deletion at 8q23.1-q24.12 associated with Langer-Giedion syndrome/ Trichorhinophalangeal syndrome (TRPS) type II and Cornelia de Lange syndrome 4.

[This corrects the article DOI: 10.1186/s13039-015-0169-9.].

An interstitial deletion at 8q23.1-q24.12 associated with Langer-Giedion syndrome/ Trichorhinophalangeal syndrome (TRPS) type II and Cornelia de Lange syndrome 4.

BACKGROUND: There are three distinct subtypes of Trichorhinophalangeal syndrome (TRPS); TRPS type I, TRPS type II and TRPS type III. Features common to all three subtypes include sparse, slowly growing scalp hair, laterally sparse eyebrows, a bulbous tip of the nose (pear-shaped), and protruding ears. Langer-Giedion syndrome (LGS) or TRPS type II is a contiguous gene syndrome on 8q24.1, involving loss of functional copies of the TRPS1 and EXT1 genes. We report a male patient that was referred to the Department of Medical Genetics due to hypotonia and dysmorphic facial features. RESULTS: Cytogenetic and array- Comparative Genomic Hybridization (aCGH) analysis revealed that the patient was a carrier of an interstitial deletion at 8q23.1-q24.12 of 12,5 Mb. Parental karyotype indicated that the father carried an apparently balanced insertion: 46, ΧΥ, der(10)ins(10;8)(q22;q23q24). CONCLUSIONS: This is the first report of an apparently balanced insertion including chromosomes 8 and 10 contributing to the etiology of LGS/ TRPS type II. Τimely diagnosis of parental balanced chromosomal rearrangements can reduce the risk of subsequent miscarriages as well as abnormal offspring.

Investigation of FANCA mutations in Greek patients.

BACKGROUND: Fanconi anemia (FA) is a rare genetic disease characterized by considerable heterogeneity. Fifteen subtypes are currently recognised and deletions of the Fanconi anemia complementation group A (FANCA) gene account for more than 65% of FA cases. We report on the results from a cohort of 166 patients referred to the Department of Medical Genetics of Athens University for genetic investigation after the clinical suspicion of FA. MATERIALS AND METHODS: For clastogen-induced chromosome damage, cultures were set up with the addition of mitomycin C (MMC) and diepoxybutane (DEB), respectively. Following a positive cytogenetic result, molecular analysis was performed to allow identification of causative mutations in the FANCA gene. RESULTS: A total of 13/166 patients were diagnosed with FA and 8/13 belonged to the FA-A subtype. A novel point mutation was identified in exon 26 of FANCA gene. CONCLUSION: In our study 62% of FA patients were classified in the FA-A subtype and a point mutation in exon 26 was noted for the first time.