Effect of inbreeding on intellectual disability revisited by trio sequencing

Abstract

In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near‐ and middle‐east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole‐exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6‐fold, and about 4.1 to 4.25‐fold for children of first‐cousin unions. These results do not rhyme with recent opinions that consanguinity‐related health risks are generally small and have been “overstated” in the past.

Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

“…Boxed parts indicate structural TAF1 domains of known functions (RefSeq: NM_004606.4). TAF1, TATA-box binding protein associated factor 1 2017; He et al, 2015;Hu et al, 2016;Kahrizi et al, 2019;Kosmicki et al, 2017;Niranjan et al, 2015;O'Rawe et al, 2015;Okamoto, Arai, Onishi, Miyake, & Matsumoto, 2019), including those currently annotated in the Human Genome Mutation Database v.2019.1 (Stenson et al, 2014). Twelve variants were maternally inherited; ten variants were de novo, including two identified in female patients (Family 6 and 12), with significantly skewed XCI (>90:10) in the one female (Individual 6) who could be tested.…”

Confirmation that variants in TTI2 are responsible for autosomal recessive intellectual disability

“…On the other hand, autosomal recessive ID (ARID) is less frequently detected by WES, especially in outbred populations. For instance, prevalence of ARID is estimated at around 10% in outbred populations, while AR inheritance is identified in less than 4% of ID cases …”

“…3,4 On the other hand, autosomal recessive ID (ARID) is less frequently detected by WES, especially in outbred populations. For instance, prevalence of ARID is estimated at around 10% 5,6 in outbred populations, while AR inheritance is identified in less than 4% of ID cases. 7 This discrepancy could be partly explained by the fact that interpretation of biallelic variants is more challenging because frequencies of alleles involved in ARID are generally higher than those of variants occurring de novo.…”

Identification of disease‐causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families

“…Over the last decade, we have systematically searched for genes involved in ARID and through these activities we have identified a large number of novel disease genes. 6,7 We here report on five Iranian ARID families which carry variants in the EXOSC gene family. Genes belonging to the exosome subunit family are involved in various RNA processes.…”