Genetics of intellectual disability in consanguineous families

Abstract

Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.

Iranome: A catalog of genomic variations in the Iranian population

“…ROH regions are considered to have functional significance in populations and are considered to be potential target regions having a tendency for rare and common disorders (Magi et al, ). Long ROHs are a consequence of recent parental relatedness and therefore can be observed more frequently in inbred populations, and are more likely to surround causative variants in individuals coming from such populations (Hu et al, ).…”

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

“…Seven families have homozygous variants in potentially novel candidate genes for ARID ( CACNG7, CARNMT1 / C9orf41, EI24, GARNL3, FXR1, TRAPPC10, TET3 ; Tables 1, 2). One additional family MR60 with severe ARID has a homozygous stop variant in GRAMD1B and a rare, damaging mis-sense variant in TBRG1 , both of which lie within the mapped region in chromosome 11q23.2-q24.2 and were previously suggested to be candidate genes for ARID (Reuter et al 2017; Hu et al 2018) having been identified in a single ARID family (Table 2). Both replicated ID genes are likely to be sufficient to cause disease etiology but no conclusion can be made on the impact on the phenotype of being a homozygous carrier for variants in both genes.…”

“…In a previous publication a missense variant within GRAMD1B was identified in a consanguineous Syrian family with moderate nonsyndromic ID (Reuter et al 2017). On the other hand, a consanguineous Persian family was found to have a frameshift TBRG1 variant co-segregating with severe ARID and developmental delay (Hu et al 2018). Two out of three affected siblings from family MR60 have severe nonsyndromic ID, but one affected sibling has severe ID with psychomotor delay (Table 1).…”

“…Additionally a TBRG1 frameshift variant was identified in a single consanguineous Persian family with severe ARID and severe developmental delay including motor and speech abnormalities (Hu et al 2018) …”

“…In several published cohorts consisting of predominantly consanguineous ARID families from the Middle East and Pakistan (number of families ranging from 18 to 337), detection rates of putatively causal variants from NGS studies range from 37 to 90% and an aggregate of 327 novel or candidate ARID genes were identified (Najmabadi et al 2011; Yavarna et al 2015; Charng et al 2016; Megahed et al 2016; Riazuddin et al 2017; Anazi et al 2017; Reuter et al 2017; Harripaul et al 2017; Monies et al 2017; Hu et al 2018). …”