Molecular characterization of a complex small supernumerary marker chromosome derived from chromosome 18p: an addition to the literature.

BACKGROUND: Small supernumerary marker chromosomes (sSMC) are a heterogeneous group of structurally abnormal chromosomes, with an incidence of 0,044% in newborns that increases up to almost 7 times in developmentally retarded patients. sSMC from all 24 chromosome have been described, most of them originate from the group of the acrocentric, with around half deriving from the chromosome 15. Non-acrocentric sSMC are less common and, in the 30 percent of the cases, are associated with phenotypic effect. Complex sSMC consist of chromosomal material derived from more than one chromosome. Genotype-phenotype correlations in patients with sSMC are difficult to assess. Clinical features depend on factors such as its size, genetic content, the involvement of imprinted genes which may be influenced by uniparental disomy and the level of mosaicism. Trisomy of the short arm of chromosome 18 (18p) is an infrequent finding and does not appear to be associated with a specific syndrome. However, mild intellectual disability with or without other anomalies is reported in almost one-third of the patients. CASE PRESENTATION: Here we present clinical and molecular characterization of a new case of de novo complex sSMC consisting of the entire short arm of chromosome 18p associated with a centromere of either chromosome 13 or 21, evidenced in a 5-year-old boy during diagnostic workup for moderate intellectual disability and dysmorphisms. To date, only seven cases of isolated trisomy 18p due to a sSMC have been reported, three of which have been characterized by array CGH. In two of them the breakpoints and the size of the duplication have been described. In the manuscript we also reviewed cases reported in the DECIPHER database carrying similar duplication and also considered smaller duplications within the region of interest, in order to evaluate the presence of critical regions implicated in the pathological phenotype. CONCLUSIONS: Our case provides additional information about phenotypic effects of pure trisomy 18p, confirms chromosomal microarray analysis as gold standard to characterize complex sSMC, and supplies additional elements for genetic counselling.

Testing single/combined clinical categories on 5110 Italian patients with developmental phenotypes to improve array-based detection rate.

BACKGROUND: Chromosomal microarray analysis (CMA) is nowadays widely used in the diagnostic path of patients with clinical phenotypes. However, there is no ascertained evidence to date on how to assemble single/combined clinical categories of developmental phenotypic findings to improve the array-based detection rate. METHODS: The Italian Society of Human Genetics coordinated a retrospective study which included CMA results of 5,110 Italian patients referred to 17 genetics laboratories for variable combined clinical phenotypes. RESULTS: Non-polymorphic copy number variants (CNVs) were identified in 1512 patients (30%) and 615 (32%) present in 552 patients (11%) were classified as pathogenic. CNVs were analysed according to type, size, inheritance pattern, distribution among chromosomes, and association to known syndromes. In addition, the evaluation of the detection rate of clinical subgroups of patients allowed to associate dysmorphisms and/or congenital malformations combined with any other single clinical sign to an increased detection rate, whereas non-syndromic neurodevelopmental signs and non-syndromic congenital malformations to a decreased detection rate. CONCLUSIONS: Our retrospective study resulted in confirming the high detection rate of CMA and indicated new clinical markers useful to optimize their inclusion in the diagnostic and rehabilitative path of patients with developmental phenotypes.

De novo chromosomal abnormalities and month of conception.

OBJECTIVES: We set out to study the possible relationship between the occurrence of chromosomal abnormalities and the month of conception using data from 7 years of prenatal diagnosis. METHODS: The sample included 7439 cytogenetic analyses from amniocentesis performed for conceptions between 1997 and 2003. The monthly prevalence of all de novo chromosomal abnormalities, trisomies, including trisomy 21, and Robertsonian translocations was investigated. RESULTS: Two hundred and four de novo numerical and structural chromosomal abnormalities (2.7%) were detected. A significant decrease in the frequencies of all de novo chromosomal abnormalities for June conceptions, as well as lower summer occurrences of trisomy 21, were found. In addition, de novo Robertsonian translocations were unexpectedly detected only among December conceptions. CONCLUSIONS: The relationship between chromosomal abnormalities and the month of conception could turn out to be useful in estimating the actual risk in pregnancy, if confirmed by other studies. The observed June lowest rate might indicate an association between chromosomal abnormalities and the maximum number of daylight hours throughout the year (summer solstice). We cannot explain the unusual findings concerning Robertsonian translocations that were only found for conceptions in December. This may be related to the annual minimum daylight hours (winter solstice) as opposed to the summer solstice.