PT  - JOURNAL ARTICLE
AU  - Ricardo Harripaul
AU  - Nasim Vasli
AU  - Anna Mikhailov
AU  - Muhammad Arshad Rafiq
AU  - Kirti Mittal
AU  - Christian Windpassinger
AU  - Taimoor I. Sheikh
AU  - Abdul Noor
AU  - Huda Mahmood
AU  - Samantha Downey
AU  - Maneesha Johnson
AU  - Kayla Vleuten
AU  - Lauren Bell
AU  - Muhammad Ilyas
AU  - Falak Sher Khan
AU  - Valeed Khan
AU  - Mohammad Moradi
AU  - Muhammad Ayaz
AU  - Farooq Naeem
AU  - Abolfazl Heidari
AU  - Iltaf Ahmed
AU  - Shirin Ghadami
AU  - Zehra Agha
AU  - Sirous Zeinali
AU  - Raheel Qamar
AU  - Hossein Mozhdehipanah
AU  - Peter John
AU  - Asif Mir
AU  - Muhammad Ansar
AU  - Leon French
AU  - Muhammad Ayub
AU  - John B. Vincent
TI  - Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families
AID  - 10.1101/092346
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 092346
4099  - http://biorxiv.org/content/early/2017/03/15/092346.short
4100  - http://biorxiv.org/content/early/2017/03/15/092346.full
AB  - Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are 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 in 192 multiplex Pakistani and Iranian consanguineous families with 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 showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.