Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability

Abstract

Recently, the application of array-based comparative genomic hybridization (array CGH) has improved rates of detection of chromosomal imbalances in individuals with mental retardation and dysmorphic features. Here, we describe three individuals with learning disability and a heterozygous deletion at chromosome 17q21.3, detected in each case by array CGH. FISH analysis demonstrated that the deletions occurred as de novo events in each individual and were between 500 kb and 650 kb in size. A recently described 900-kb inversion that suppresses recombination between ancestral H1 and H2 haplotypes encompasses the deletion. We show that, in each trio, the parent of origin of the deleted chromosome 17 carries at least one H2 chromosome. This region of 17q21.3 shows complex genomic architecture with well-described low-copy repeats (LCRs). The orientation of LCRs flanking the deleted segment in inversion heterozygotes is likely to facilitate the generation of this microdeletion by means of non-allelic homologous recombination.

Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism

“…1 A distinct MAPT haplotype, H2, in one of the parents has been suggested to be a prerequisite to facilitate the microdeletion. [5][6][7]11 The H2 haplotype is detected in 20% of the independent chromosomes, in the Utah HapMap project sample of individuals of the Northern and Western European ancestry, and is linked to an inversion polymorphism of B900 kb. 9 In family 1, the mother of the siblings is a H1/H2 heterozygote.…”

“…[1][2][3][4] The syndrome is caused by a recurrent 500-650 kb heterozygous deletion at chromosome 17q21.31, [5][6][7] which is thought to result from nonallelic homologous recombination (NAHR), 8 mediated by flanking low-copy repeats. The minimum critical region is 424 kb (41 046 729-41 470 954 Mb, hg18) in size 1 and encompasses four known genes, CRHR1, IMP5, MAPT, and STH, in addition to three putative genes, FLJ25168, BC018035, and LOC284058.…”

The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant

“…A search of the medical literature identified 23 articles describing the clinical features of 81 patients with KdVS. [1][2][3][4][5]13,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] …”

“…[1][2][3] The syndrome can be either caused by a microdeletion in chromosomal region 17q21. 31 or by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene (NG_032784.1).…”

Human genomics: The genome finishers

“…An alternative haplotype, a complex inversion of the first that is found in 20% of Europeans, was shown in 2005 to correlate with larger family sizes, suggesting that this second haplotype was under some form of positive selection 7 . But in 2006, Evan Eichler 8 , a geneticist at the University of Washington in Seattle, and two other groups 9,10 showed that the inverted region was also prone to frequent spontaneous deletions that led to mental retardation. The inverted haplotype seemed to be both adaptive and the source of debilitating deletions.…”