RT Journal Article
SR Electronic
T1 Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 092346
DO 10.1101/092346
A1 Ricardo Harripaul
A1 Nasim Vasli
A1 Anna Mikhailov
A1 Muhammad Arshad Rafiq
A1 Kirti Mittal
A1 Christian Windpassinger
A1 Taimoor Sheikh
A1 Abdul Noor
A1 Huda Mahmood
A1 Samantha Downey
A1 Maneesha Johnson
A1 Kayla Vleuten
A1 Lauren Bell
A1 Muhammad Ilyas
A1 Falak Sher Khan
A1 Valeed Khan
A1 Mohammad Moradi
A1 Muhammad Ayaz
A1 Farooq Naeem
A1 Abolfazl Heidari
A1 Iltaf Ahmed
A1 Shirin Ghadami
A1 Zehra Agha
A1 Sirous Zeinali
A1 Raheel Qamar
A1 Hossein Mozhdehipanah
A1 Peter John
A1 Asif Mir
A1 Muhammad Ansar
A1 Leon French
A1 Muhammad Ayub
A1 John B Vincent
YR 2016
UL http://biorxiv.org/content/early/2016/12/08/092346.abstract
AB Approximately 1% of the population worldwide are affected by intellectual disability (ID), the vast majority of whom currently receive no molecular diagnosis. Previous studies indicate high levels of genetic heterogeneity, with estimates of over 2500 autosomal ID genes, with the majority being autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations for 192 multiplex Pakistani and Iranian consanguineous families ascertained for non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families, in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7, and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene-sets for other neuropsychiatric disorders. Transcriptional studies show prominent expression in the prenatal brain. The high yield of AR mutations for ID signals that this approach has excellent clinical potential, will inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations where consanguinity is common. As with other AR disorders, the relevance will also impact outbred populations.