Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports

TLDR

Chromosomal abnormalities are a major cause of mental retardation and multiple congenital anomalies, and prior array CGH studies have estimated a 10‑15 % incidence of previously unnoticed de novo chromosomal imbalances in patients with normal karyotypes. The study reports array CGH screening of 140 idiopathic MCA/MR patients with normal karyotypes, the largest series published to date. Array CGH at ≥1 Mb resolution was applied to 432 MCA/MR patients, including a series of 140 idiopathic cases with normal karyotypes. Array CGH identified submicroscopic imbalances in 20 % of the 140 patients (including 18 deletions, 7 duplications, and 3 translocations), with 17 de novo and 19 likely causal alterations, and revealed that 8.8 % of 432 MCA/MR patients harbor de novo intrachromosomal changes, most of which are non‑recurrent and spread across the genome, underscoring array CGH as essential for detecting clinically relevant and mosaic chromosomal abnormalities.

Abstract

Chromosomal abnormalities are a major cause of mental retardation and multiple congenital anomalies (MCA/MR). Screening for these chromosomal imbalances has mainly been done by standard karyotyping. Previous array CGH studies on selected patients with chromosomal phenotypes and normal karyotypes suggested an incidence of 10-15% of previously unnoticed de novo chromosomal imbalances.To report array CGH screening of a series of 140 patients (the largest published so far) with idiopathic MCA/MR but normal karyotype.Submicroscopic chromosomal imbalances were detected in 28 of the 140 patients (20%) and included 18 deletions, seven duplications, and three unbalanced translocations. Seventeen of 24 imbalances were confirmed de novo and 19 were assumed to be causal. Excluding subtelomeric imbalances, our study identified 11 clinically relevant interstitial submicroscopic imbalances (8%). Taking this and previously reported studies into consideration, array CGH screening with a resolution of at least 1 Mb has been undertaken on 432 patients with MCA/MR. Most imbalances are non-recurrent and spread across the genome. In at least 8.8% of these patients (38 of 432) de novo intrachromosomal alterations have been identified.Array CGH should be considered an essential aspect of the genetic analysis of patients with MCA/MR. In addition, in the present study three patients were mosaic for a structural chromosome rearrangement. One of these patients had monosomy 7 in as few as 8% of the cells, showing that array CGH allows detection of low grade mosaicisims.