Laurence Taine

Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype–phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within ∼85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.

Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome (RTS, MIM 180849) occurs in 1/125 000 births and is characterised by growth retardation and psychomotor developmental delay, broad and duplicated distal phalanges of the thumbs and halluces, typical facial dysmorphism, and an increased risk of neoplasia.1 RTS has been shown to be associated with chromosomal rearrangements in cytogenetic band 16p13.3,2–4 all involving the CREB binding protein gene, officially named CREBBP by the HUGO Nomenclature Committee, but generally referred to by its shorter acronym CBP .5 CBP is a transcriptional coactivator involved in different signal transduction pathways, thereby regulating the expression of many genes and playing an important role in the regulation of cell growth, cellular differentiation, and tumour suppression.6,7 To date, all studies concerning CBP in RTS have used FISH analysis with cosmids from the CBP region or the search for mutations at the molecular level using the protein truncation test.8,9 Taken together, these studies showed that translocations and inversions form the minority of CBP mutations in RTS, microdeletions account for only 10% of RTS cases, and PTT studies showed 10% truncating mutations. The structure of the CBP gene was recently described.8 CBP spans about 150 kb with 31 exons and its cDNA is 9 kb in length. We report here the use of different molecular techniques to analyse the CBP gene in a cohort of 60 RTS patients. These include cDNA probes to search for gross rearrangements by Southern blot analysis and to identify CBP mRNA of abnormal sizes on northern blots, intragenic microsatellite markers to look for intragenic deletions, as well as a complete series of primers to PCR amplify each of the 31 exons of the gene for mutation searching by direct sequencing. We have analysed 60 patients using these various techniques and identified 27 …

Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH

Autism is a rare neurodevelopmental disorder with a strong genetic component. Co-occurrence of autism and chromosomal abnormalities is useful to localize candidate regions that may include gene(s) implicated in autism determinism. Several candidate chromosomal regions are known, but association of chromosome 22 abnormalities with autism is unusual. We report a child with autistic syndrome and a de novo 22q13.3 cryptic deletion detected by FISH. Previously described cases with 22q13.3 deletions shared characteristic developmental and speech delay, but autism was not specifically reported. This case emphasizes a new candidate region that may bear a gene involved in autism etiopathogenesis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:839-844, 2000.

The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients.

The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable ‘2q37-deletion syndrome’ or Albright’s hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8 Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype–phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1.

Submicroscopic deletion of chromosome 16p13.3 in patients with Rubinstein-Taybi syndrome.

The Rubinstein-Taybi syndrome (RTS) is a well-defined entity characterized by growth and mental retardation, broad thumbs and halluces, and typical face. The RTS locus was assigned to 16p13.3, and interstitial submicroscopic deletions of this region (RT1 cosmid, D16S237) were initially identified in 25% of RTS patients. The gene for the human CREB binding protein, the transcriptional coactivator CBP, is included in the RT1 cosmid, and mutations in CBP have recently been identified in nondeleted RTS patients. We investigated 30 French patients with RTS. Among these patients, 3 had the RT1 microdeletion (frequency 10%). There is no obvious phenotypic difference between the patients with and without the RT1 deletion. The RT1 probe appears useful for confirmation of the diagnosis but is of little interest as a screening tool. By pooling data including the previous series and our current series, the cumulative frequency of the 16p13.3 microdeletion is 11.9% (19 in 159). This frequency of approximately 12% deleted patients appears more accurate than the 25% previously reported. Molecular investigations of CBP are in process in our series to clarify the cause of RTS.

Pregnancy Outcome and Prognosisin Fetuses with Increased First-TrimesterNuchal Translucency

Objective: One of the concerns of prenatal diagnosis is to find sensitive markers to screen for chromosome abnormalities, such as serum assays or nuchal translucency (NT). This study reports our experience with NT measurement during the first trimester of pregnancy. Materials: The study was performed prospectively on 252 fetuses with either NT ≧3 mm or cystic hygroma. Results: We observed 50 abnormal karyotypes, i.e. 19.8%. The incidence of chromosome abnormalities increased with increasing maternal age and increasing NT thickness. For the 202 fetuses with normal karyotypes, outcome was unfavourable in 32 cases: 23 elective terminations of pregnancy, 8 spontaneous abortions and 1 neonatal death. Outcome was favourable in 141 cases. Twenty-nine pregnancies were lost to follow-up. Conclusion: Measurement of NT at 12 weeks’ gestation seems to be a good marker for chromosome abnormalities. When the karyotype is normal, the pregnancy outcome remains correlated with the degree of NT thickness. The finding of NT >3 mm between 10 and 14 weeks’ gestation dictates rigorous ultrasound monitoring and caution when predicting pregnancy outcome.

Early-onset obesity and paternal 2pter deletion encompassing the ACP1 , TMEM18 , and MYT1L genes

Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader–Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.

Chromosome analysis of adenomatous polyps of the colon: Possible existence of two differently evolving cytogenetic groups

A chromosomal study of 42 colonic adenomatous polyps was performed using a technique of direct chromosome analysis derived from the prenatal procedure for diagnosing chromosomal alterations from chorionic villi sampling. Abnormal karyotypes were found in 22 cases. Trisomy 7, the most frequently found alteration, was found in 13 cases, followed by trisomy 13 (nine cases). Monosomy 18 was observed in two cases; in one of these, that of a polyp which had degenerated into an intra-mucosal adenocarcinoma, it was associated with 17p monosomy. Interestingly, these two types of alterations (trisomy 7 versus 18 and 17p monosomy) were not found together in the same lesion. This suggests that there could be two distinct chromosomal behaviors which might be related to the two cytogenetic groups described for colorectal adenocarcinoma. However, the respective frequencies of such cytogenetic groups varied inversely between adenomas and adenocarcinomas, thus suggesting that they evolve differently.

Use of a set of highly polymorphic minisatellite probes for the identification of cryptic 1p36.3 deletions in a large collection of patients with idiopathic mental retardation.

Editor—Mental retardation is a component of a large number of syndromes, most of which qualify individually as rare genetic diseases. Altogether, mental retardation affects 2-3% of the population and is unexplained in 40% of cases. According to Knight et al ,1 subtle telomeric chromosomal rearrangements are responsible for approximately 1% of unexplained mental retardation (with the proportion being highest, 7.4%, in the subclass of unexplained moderate to severe mental retardation). The identification of the genes responsible will require the precise delimitation of minimum deletion regions, which relies upon the collection of a large number of cases. Because of the low expected frequency of each telomeric deletion in mental retardation, the procedure to be applied should allow the screening of many patients at a low cost. It is not yet clear whether all chromosome ends are associated with mental retardation syndromes with similar frequency. Distal chromosome 1p36 deletions were initially detected cytogenetically because of an associated segmental imbalance.2-5 This syndrome results from both interstitial and terminal deletions of varying sizes and different breakpoints6 and the severity of the phenotype is related to the extent of the deletion.7 Clinical examination can efficiently detect a large proportion of cases, so that the number of reports of 1p36 deletions has increased significantly in the past few years which may give the false impression that this is a relatively frequent syndrome. We show here how highly polymorphic minisatellites located within a short region can provide an efficient prescreening of samples without the need for parental samples at the initial stage. The procedure was tested here using 1p36 minisatellites and provides an estimate of the frequency of 1p36 deletions in mentally retarded patients. A selection of five highly polymorphic minisatellite probes was used to search for 1p36.3 deletions in a …

Combination of WAGR and Potocki–Shaffer contiguous deletion syndromes in a patient with an 11p11.2–p14 deletion

Aniridia, Wilms tumor, genitourinary abnormalities, growth and mental retardation are the cardinal features of the WAGR 11p13 deletion syndrome. The Potocki–Schaffer syndrome or proximal 11p deletion syndrome (previously DEFECT11 syndrome) is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses and enlarged parietal foramina. Mental handicap, facial dysmorphism and craniosynostosis may also be associated. We report a patient with combined WAGR and Potocki–Shaffer syndromes, and obesity. She presented with aniridia, cataract, nystagmus, corneal ulcers and bilateral congenital ptosis. A left nephroblastoma was detected at 15 months. Other features included moderate developmental delay, growth deficiency, facial dysmorphism, multiple exostoses and cranial lacunae. High-resolution and molecular cytogenetics confirmed a del(11)(p11.2p14.1) deletion with a proximal breakpoint between the cosmid DO8153 and the BAC RP11-104M24 to a distal breakpoint between cosmids CO8160 (D11S151) and F1238 (D11S1446). The deletion therefore includes EXT2, ALX4, WT1 and PAX6. This case appears to be the second patient reported with this combined deletion syndrome and confirms the association of obesity in the WAGR spectrum, a feature previously reported in four cases, and for which the acronym WAGRO has been suggested. Molecular and follow-up data on the original WAGRO case are briefly presented.