Expanding the genetic heterogeneity of intellectual disability

Abstract

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

Expanding the clinical and genetic spectra of NKX6‐2‐related disorder

“…All variants identified by the present study were found in patients of Middle East origin. Two of them were observed more than once (Figure ), and these 2 variants have previously been reported from Saudi Arab patients . This fact, along with our haplotyping data for carriers of the c.196delC variant (Figure S1A), supports the hypothesis of founder variants to contribute to NKX6‐2 ‐related disease .…”

“…The clinical findings were rather uniform in our cohort of patients (Table ). Regarding age at onset and severity, our patients and most of those reported previously are highly similar . A notable exception are 2 families that carry the c.121A>T (p.(Lys41*)) variant.…”

“…Many genetic HLDs still remain undiagnosed, but the advances in NGS have strongly reduced the number of unsolved/unsolvable cases . NKX6‐2 is one of the most recent additions to the growing list of potential HLD genes . Our study involves 6 novel families and the largest cohort of patients reported to date; it thereby represents final proof for a causal connection between biallelic NKX6‐2 variants and HLD.…”

“…Biallelic variants in NKX6‐2 (OMIM *605955; OMIM #617560) are one of the most recently identified causes of HLD. Three studies almost simultaneously reported a total of 15 pertinent patients from 7 families in 2017 . Although overall clinical and imaging data were consistent with HLD, 1 of the 2 larger studies characterized the disease as very severe, while the other emphasized a comparatively mild phenotype in 2 of 3 families presented .…”

Genetic investigation of 93 families with microphthalmia or posterior microphthalmos

“…As expected in a highly consanguineous population (we note that 33% of our cohort was non‐consanguineous but endogamy cannot be ruled out in those cases), recessive causes accounted for the majority. We have seen this pattern repeatedly across other genetically heterogeneous diseases of the eye (retinal dystrophy and cataract), as well as other organs (intellectual disability) . In their review, Williamson and Fitzpatrick suggested that some of the recessive causes ( C12orf57 and ODZ3 , specifically) remain unconfirmed .…”