Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation

Abstract

The underlying cause of mental retardation remains unknown in up to 80% of patients. As chromosomal aberrations are the most common known cause of mental retardation, several new methods based on FISH, PCR, and array techniques have been developed over recent years to increase detection rate of subtle aneusomies initially of the gene rich subtelomeric regions, but nowadays also genome wide. As the reported detection rates vary widely between different reports and in order to compare the diagnostic yield of various investigations, we analyzed the diagnostic yield of conventional karyotyping, subtelomeric screening, molecular karyotyping, X‐inactivation studies, and dysmorphological evaluation with targeted laboratory testing in unselected patients referred for developmental delay or mental retardation to our cytogenetic laboratory (n = 600) and to our genetic clinic (n = 570). In the cytogenetic group, 15% of patients showed a disease‐related aberration, while various targeted analyses after dysmorphological investigation led to a diagnosis in about 20% in the genetic clinic group. When adding the patients with a cytogenetic aberration to the patient group seen in genetic clinic, an etiological diagnosis was established in about 40% of the combined study group. A conventional cytogenetic diagnosis was present in 16% of combined patients and a microdeletion syndrome was diagnosed in 5.3%, while subtelomeric screening revealed only 1.3% of causes. Molecular karyotyping with a 10 K SNP array in addition revealed 5% of underlying causes, but 29% of all diagnoses would have been detectable by molecular karyotyping. In those patients without a clear diagnosis, 5.6% of mothers of affected boys showed significant (>95%) skewing of X‐inactivation suggesting X‐linked mental retardation. The most common diagnoses with a frequency of more than 0.5% were Down syndrome (9.2%), common microdeletion 22q11.2 (2.4%), Williams–Beuren syndrome (1.3%), Fragile‐X syndrome (1.2%), Cohen syndrome (0.7%), and monosomy 1p36.3 (0.6%). From our data, we suggest the following diagnostic procedure in patients with unexplained developmental delay or mental retardation: (1) Clinical/dysmorphological investigation with respective targeted analyses; (2) In the remaining patients without an etiological diagnosis, we suggest conventional karyotyping, X‐inactivation screening in mothers of boys, and molecular karyotyping, if available. If molecular karyotyping is not available, subtelomeric screening should be performed. © 2006 Wiley‐Liss, Inc.

High-resolution SNP arrays in mental retardation diagnostics: how much do we gain?

“…After digestion, an adaptor was linked to the restricted fragments, the reaction was diluted 4Â and the fragments were amplified by PCR. After purification using Magnetic Beads (Agencourt Bioscience Corporation, Beverly, MA, USA), 90 mg of PCR products was fragmented and end labeled using 30 U/ml of terminal deoxynucleotidyl transferase, and then hybridized for [16][17][18] h to the Affymetrix 6.0 chip at 491C in a GeneChip Hybridization Oven 640 (Affymetrix). The chips were washed, stained in GeneChip Fluidic Station 450 (Affymetrix) and scanned with Scanner 3000 7G (Affymetrix).…”

“…15 Genetic causes account for 17.4-47.1% of cases, with reported frequencies also varying on the basis of the different techniques used for analysis. 15,16 Several years ago, microarray platforms were used for the first time in clinical genetics, showing that abnormalities in genomic copy number account for about 10-15% of patients affected by MR, especially when it is associated with multiple congenital anomalies (MCA) and/or dysmorphism. 17 Microarrays represent a robust and high-resolution method of analysis.…”

Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability

“…2 Despite this, more than 60% of patients have no identifiable genetic cause. 3 The recent introduction of next-generation sequencing technologies has opened new possibilities, making the detection of causal variants more economical and faster. Recent studies have revealed that a significant proportion of sporadic ID might be attributable to de novo mutations, 4,5 whereas only a small number has shown recessive inheritance.…”

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

“…In a representative study, Rauch et al 2 showed that 15% of the cases of ID are due to cytogenetic anomalies, and that further 15% are due to submicroscopic aberrations. X-chromosomal mutations are possibly the cause in about 10% of the cases.…”