Recurrent HERV-H-Mediated 3q13.2-q13.31 Deletions Cause a Syndrome of Hypotonia and Motor, Language, and Cognitive Delays

Abstract

We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays and also variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include down-slanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus (HERV-H) elements ∼5kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested non-allelic homologous recombination (NAHR) between HERV-H elements as a mechanism of deletion formation, analogous to HERV-I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease.

Dosage Changes of a Segment at 17p13.1 Lead to Intellectual Disability and Microcephaly as a Result of Complex Genetic Interaction of Multiple Genes

“…11 In our cohort, rearrangements generated by recombination between repetitive elements predominate: repetitive elements were present at both breakpoints in three out of four deletions (75%) that had breakpoints sequenced; two out of four (50%) deletions were mediated by these elements (DECIPHER2173, AluSg-AluY with 82% of nucleotide similarity and BAB3277, LTR13A-LTR13A with 96% of nucleotide similarity). Deletions mediated by repetitive elements have been observed for a number of genomic disorder-associated loci, often nonrecurrent rearrangements: for example, deletions observed in rare pathogenic CNVs, 53 55 although recurrent rearrangements are also observed, as the 3.4 Mb HERV-H-mediated 3q13.2-q13.31 deletions that lead to a syndrome marked by motor and language delay, 56 and the HERV-I-mediated AZFa deletion that causes Y-linked spermatogenic failure (SPGFY2 [MIM 415000]). 57,58 In addition to repetitive-element-mediated events, the complex rearrangement including the segmental insertion of 76 nt from a nearby AluY element in BAB3036 suggests that replication-based mechanisms, such as fork stalling and template switching (FoSTeS) or microhomology-mediated-break-induced replication (MMBIR), 28,59,60 also underlie rearrangements involving 17p13.1.…”

Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis

“…However, the translocation partners are different chromosomes. Recombination between HERV-H repeats has been implicated in other translocations and deletions (Hermetz et al 2012;Shuvarikov et al 2013;Campbell et al 2014). Robberecht Case 7 has an unbalanced translocation likely mediated by NAHR between L1PA4 elements on Chromosomes 9 and 10.…”

Molecular functions of human endogenous retroviruses in health and disease

“…For example, HERV-H (ERVH)-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays [184].…”