Aziza Lebbar

Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome

Histone deacetylase 4 (HDAC4) serves important roles in multiple human systems, including neurological, cardiac, and skeletal functions. Mutation or deletion of HDAC4 causes brachydactyly mental retardation syndrome (BDMR), a disorder that includes intellectual disability, behavioral abnormalities, autism spectrum disorder, and craniofacial and skeletal anomalies, including brachydactyly type E. We present a case of familial BDMR, including a parent with mild symptoms of the disorder and a child exhibiting a more severe phenotype. Cytogenetic testing showed a cryptic balanced translocation in the mother that resulted in a 2q37.1 monosomy and a 10q26.1 trisomy in the son. Gene expression analyses demonstrated 67% HDAC4 expression in the mother and 23% HDAC4 expression in the son relative to normal controls, lending evidence to the hypothesis that HDAC4 modulates severity of this disorder in a dosage‐dependent manner.

Molecular cytogenetic characterization of the first reported case of inv dup del 20p compatible with a U‐type exchange model

Inverted duplications with terminal deletions have been reported for an increasing number of chromosome ends. The best characterized and most frequent rearrangement reported involves the short arm of chromosome 8. It derives from non‐allelic homologous recombination (NAHR) between two inverted LCRs (low copy repeats) of the olfactory receptor (OR) gene cluster during maternal meiosis. We report here on the cytogenetic characterization of the first inversion duplication deletion involving the short arm of chromosome 20 (inv dup del 20p) in an 18‐month‐old boy presenting with clinical signs consistent with 20p trisomy syndrome. This abnormality was suspected on karyotyping, but high‐resolution molecular cytogenetic investigations were required to define the breakpoints of the rearrangement and to obtain insight into the mechanism underlying its formation. The duplicated region was estimated to be 18.16 Mb in size, extending from 20p13 to 20p11.22, and the size of the terminal deletion was estimated at 2.02 Mb in the 20p13 region. No single copy region was detected between the deleted and duplicated segments. As neither LCR nor inversion was identified in the 20p13 region, the inv dup del (20p) chromosome abnormality probably did not arise by NAHR. The most likely mechanism involves a break in the 20p13 region, leading to chromosome instability and reparation by U‐type exchange or end‐to‐end fusion.

Fetal Loss after Amniocentesis in a Series of 5,780 Procedures

Objectives: Counseling on prenatal diagnosis requires accurate knowledge of the associated risks, including fetal loss. The objective of our study was to assess this risk of amniocentesis in a single center with several operators. Methods: This retrospective analysis concerns only women with singleton pregnancies who underwent amniocentesis between 14+0 and 23+6 weeks’ gestation. Results: During this 4.5-year period, 5,780 amniocenteses were performed, of which we analyzed 5,319. The rate of fetal loss was 70 in 4,858 tests (1.4%), with a lost-to-follow-up rate of 3.8%. Conclusion: Our results for fetal loss are comparable to those in the largest series with fewer operators already published.

First reported case of intrachromosomal cryptic inv dup del Xp in a boy with developmental retardation.

We report here on a 6‐year‐old boy referred to the laboratory for karyotyping and SHOX microdeletion testing. The most significant clinical findings in this boy were small stature, Madelung deformity, facial dysmorphism, mild mental retardation and behavioral problems. R‐, G‐ and RTBG‐banding chromosome analysis showed a normal male karyotype. Fine molecular characterization, by FISH, of terminal Xp microdeletion revealed an associated partial duplication. Further refinement of the molecular analysis indicated an inverted duplication of the Xp22.31–Xp22.32 (13.7 Mb) region including the STS, VCX‐A and KAL1 genes, associated with a terminal Xp deletion Xp22.33‐Xpter (3.6 Mb) encompassing the SHOX and ARSE genes. Such rearrangements have been characterized for other chromosomal pairs, but this is the first reported male patient involving the short arm of the X chromosome. Molecular analysis of the maternal and patients microsatellite markers showed interchromatid mispairing leading to non‐allelic homologous recombination to be the most likely mechanism underlying this rearrangement. This case highlights the importance of clinically driven FISH investigations in order to uncover cryptic micro‐rearrangements.

Is Rapid Aneuploidy Screening Used Alone Acceptable in Prenatal Diagnosis? An Evaluation of the Possible Role of Ultrasound Examination

Objective: The objectives of this study were to use a factual basis to: (1) determine the number, nature, and probable phenotypic consequences of karyotype anomalies that would probably be missed (structural anomalies, uncommon aneuploidies and mosaic aneuploidies) by rapid aneuploidy screening (RAS), and (2) appraise whether RAS can replace traditional karyotyping when amniocenteses are performed for increased risk of Down’s syndrome by maternal serum screening or advanced maternal age in the absence of ultrasound abnormality. Methods: This retrospective cohort study analysed the indications, results and outcomes of 5,713 consecutive amniocenteses over a 5-year period at a single prenatal diagnosis centre in Paris. Results: Advanced maternal age and increased Down’s risk with maternal serum marker were the most common indications. Chromosome abnormalities were detected in 3.64% of the pregnancies tested, and unexpected structural anomalies in 0.63% (n = 36). Translocations were more likely to be reciprocal, balanced and of parental origin. There were 6 mosaic gonosomal aneuploidies. Overall, 4 mosaic autosomal aneuploidies and 36 structural aberrations would not have been recognised by RAS alone. Of the 4 mosaic autosomal aneuploidies, all were terminated, one had major malformations and the others had discrete signs that a good quality ultrasound examination would probably not detect. Of the 36 structural aberrations, 24 would be undetected by ultrasound scan, from which 6 would be associated with a significant risk of an abnormal phenotype outcome. Conclusion: In conclusion, our data do not provide evidence that RAS can replace the traditional karyotype. It is probably impossible to arrive in a universal conclusion of which approach (karyotype or RAS) is definitely better than the other. Each prenatal centre could have its own approach depending on the local data analysis, including quality control of ultrasounds.

Optimized criteria for using fluorescence in situ hybridization in the prenatal diagnosis of common aneuploidies.

To evaluate the medical and economic performance of three strategies for selecting patients eligible for interphase FISH in the prenatal diagnosis of common aneuploidies.

Clinical and molecular delineation of Tetrasomy 9p syndrome: report of 12 new cases and literature review.

Tetrasomy 9p is a generic term describing the presence of a supernumerary chromosome incorporating two copies of the 9p arm. Two varieties exist: isodicentric chromosome 9p (i(9p)), where the two 9p arms are linked by a single centromeric region, and pseudodicentric 9p (idic(9p)), where one active and one inactive centromere are linked together by a proximal segment of 9q that may incorporate euchromatic material. In living patients, i(9p) and idic(9p) are usually present in a mosaic state. Fifty‐four cases, including fetuses, have been reported, of which only two have been molecularly characterized using array‐CGH. Tetrasomy 9p leads to a variable phenotype ranging from multiple congenital anomalies with severe intellectual disability and growth delay to subnormal cognitive and physical developments. Hypertelorism, abnormal ears, microretrognathia and bulbous nose are the most common dysmorphic traits. Microcephaly, growth retardation, joint dislocation, scoliosis, cardiac and renal anomalies were reported in several cases. Those physical anomalies are often, but not universally, accompanied by intellectual disability. The most recurrent breakpoints, defined by conventional cytogenetics, are 9p10, 9q12 and 9q13. We report on 12 new patients with tetrasomy 9p (3 i(9p), 8 idic(9p) and one structurally uncharacterized), including the first case of parental germline mosaicism. All rearrangements have been characterized by DNA microarray. Based on our results and a review of the literature, we further delineate the prenatal and postnatal clinical spectrum of this imbalance. Our results show poor genotype‐phenotype correlations and underline the need of precise molecular characterization of the supernumerary marker.

Amniocentesis Performed for Karyotyping after Identified Ultrasonographic Abnormalities: What to Expect?

Objectives: The aim of this study was to evaluate the relative risk of identifying fetal chromosomal anomalies after finding ultrasonographic (US) abnormalities in a high-risk population who underwent amniocentesis. Methods: A retrospective review of a cohort of patients with single pregnancies who underwent genetic amniocentesis was undertaken. Univariate and multivariate analysis were used to determine the best correlations between US findings and chromosomal abnormalities. Results: Overall, 191 chromosomal abnormalities were found in 5,604 fetuses (3.4%). Multivariate analysis showed chromosomal abnormalities were significant ly associated with anomalies of the central nervous system (OR = 4.4, 95% CI 2.2-8.7), face and neck (OR = 15.7, 95% CI 9.2-26.8), heart (OR = 5.4, 95% CI 2.6-11.2), abdomen (OR = 5.6, 95% CI 2.9-10.9), extremities (OR = 5.7, 95% CI 2.4-13.4), an increased nuchal fold (OR = 5.2, 95% CI 3.3-8.1), an intrauterine growth restriction (OR = 3.6, 95% CI 1.6-7.9) and a short femur (OR = 4.1, 95% CI 1.4-12.1). Conclusions: Our results confirm the validity of specific US markers in detecting chromosomal abnormalities in the fetus.

Sperm FISH analysis in two healthy infertile brothers with t(15;18) unbalanced translocation: Implications for genetic counselling and reproductive management.

Numerous studies have shown that balanced reciprocal or Robertsonian translocations and inversions are associated with reduced or absent sperm production. In contrast, a similar association has been rarely reported for unbalanced translocations. An unbalanced translocation, 45,XY,-15,der(18)t(15;18)(q11.2;q23), was found in two healthy infertile brothers who were referred to our hospital together with their partners for infertility. At least two routine semen analyses and karyotyping were done for each of the brothers. Sperm meiotic segregation was studied for both with a three-color FISH assay using locus-specific probes. Semen analyses showed a severe oligo-astheno-teratozoospermia with remarkably similar profiles in the two brothers. The unbalanced translocation had a deletion of 15pter-15q11.2 as well as a deletion of 18q23-18qter. The meiotic segregation was similar in the two brothers with a prevalence of alternate segregation mode. However, no phenotypic effect in the offspring can be expected only if the normal chromosomes 15 and 18 are transmitted to progeny. According to the sperm FISH results, the theoretical probability of this happening is about 25%. Based on the overall results, genetic and reproductive counselling was offered to both couples. Finally, both couples chose the alternative of donor insemination rather than preimplantation genetic diagnosis. The present study helps delineating a phenotypically silent CNV at the distal part of chromosome 18 long arm and illustrates the advantages of an integrated multidisciplinary genetic, reproductive and psychological approach to give the best possible assistance to couples who are faced with a complex and distressing genetic cause of infertility.

Two cases of mosaicism for complex chromosome rearrangements (CCRM) associated with secondary infertility

Structural chromosomal abnormalities can be associated with infertility through meiosis impairment or the formation of unbalanced gametes. Among these structural abnormalities, complex chromosomal rearrangements (CCR) relate to situations with more than two breakpoints and/or more than two chromosomes involved. Mosaic balanced chromosomal rearrangements are very rare events usually ascertained through infertility, recurrent miscarriages or liveborn abnormal children. Mosaicism for complex chromosome rearrangements (CCRM) has never been described to date. Here we report on two patients with secondary infertility whose karyotype revealed mosaic partially cryptic CCRs, revealed by fluorescence in situ hybridization (FISH). To our knowledge, this is the first report of mosaicism for complex chromosomal rearrangements (CCRM). We discuss the importance of molecular cytogenetic characterization of structural rearrangements to assist in genetic counseling related to the possible use of assisted reproductive technology.