Transmitted cytogenetic abnormalities in patients with mental retardation: pathogenic or normal variants?

Abstract

Knowing the origin of cytogenetic abnormalities detected in individuals with mental retardation and dysmorphic features is essential to genetic counselling of affected families. To illustrate this, we report on six families with transmitted cytogenetic abnormalities and discuss the genotype-phenotype correlations, including the possibility of the abnormalities being normal genomic variants. The abnormalities were detected using metaphase HR-CGH; their size was estimated to range from 1.6 to 7.5 Mb using tiling path array-CGH and real-time PCR. The abnormalities were transmitted through two to four generations and included interstitial deletions of 1p31.3-p32.1, 2q13, 10q11.21-q11.23, and 13q31.1; a duplication of 1p34.1-p34.2; and in one family both a deletion of 18q21.1 and a duplication of 4q35.1-q35.2. The probands were mentally retarded and had nonspecific dysmorphic features except for one patient with the Bohring-Opitz syndrome. We considered the abnormalities in two families to be clinically significant: In one family, the proband's brain abnormality was comparable to previously reported abnormalities in individuals with a similar duplication of 1p31-p32. Congenital heart disease was previously mapped to the chromosomal region of 18q that was affected in the proband of another family. The carrier parents in both families had mild clinical features. In two families the abnormalities were considered as coincidental findings, and in two further families the abnormalities were insufficient to explain the phenotypes of the probands but possibly were related to a milder phenotype in other family members. These cases illustrate the need for careful assessment of the extended family in order to interpret the phenotypic consequences of abnormalities identified using array-CGH.