S. Anazi, S. Maddirevula, V. Salpietro, Y.T. Asi, S. Alsahli, A. Alhashem, H.E. Shamseldin, F. AlZahrani, N. Patel, N. Ibrahim, F.M. Abdulwahab, M. Hashem, N. Alhashmi, F. Al Murshedi, A. Al Kindy, A. Alshaer, A. Rumayyan, S. Al Tala, W. Kurdi...........
Hum Genet., (2017)
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
S. Anazi, S. Maddirevula, V. Salpietro, Y.T. Asi, S.
Alsahli, A. Alhashem, H.E. Shamseldin, F. AlZahrani, N. Patel, N. Ibrahim, F.M.
Abdulwahab, M. Hashem, N. Alhashmi, F. Al Murshedi, A. Al Kindy, A. Alshaer, A.
Rumayyan, S. Al Tala, W. Kurdi, A. Alsaman, A. Alasmari, S. Banu, T. Sultan, M.M.
Saleh, H. Alkuraya, M.A. Salih, H. Aldhalaan, T. Ben-Omran, F. Al Musafri, R. Ali,
J. Suleiman, B. Tabarki, A.W. El-Hattab, C. Bupp, M. Alfadhel, N. Al Tassan, D.
Monies, S.T. Arold, M. Abouelhoda, T. Lashley, H. Houlden, E. Faqeih, F.S. Alkuraya