Expanding the genetic heterogeneity of intellectual disability

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 genetic heterogeneity of intellectual disability

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\u2013gene 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

Correction to: Expanding the genetic heterogeneity of intellectual disability (Human Genetics, (2017), 136, 11-12, (1419-1429), 10.1007/s00439-017-1843-2)

Variant nomenclature discrepancy was identified in the article “Expanding the genetic heterogeneity of intellectual disability”, Human Genetics, November 2017, Volume 136, Issue 11-12, pp 1419-1429 after its publication. Specifically, the nomenclature of GTF3C3 was originally listed as NM_012086.4:c.1382+3A>G when it should be NM_012086.4:c.1390+3A>G, the nomenclature of MADD was originally listed as NM_001135943.1:c.2930T>G:p.(Val977Gly) when it should be NM_001135943.1:c.2930T>G:p.(Leu977Arg), and the variant NM_001164416.1:c.124C>T:p.(Arg42*) was listed under the gene's name VWA3B when it should be H2BFM. The following changes were made in the attached corrections: 1. Nomenclature of GTF3C3 is changed to NM_012086.4:c.1390+3A>G in 15DG0315 (from NM_012086.4:c.1382+3A>G) in the main text, Table S1, Table S2 and Figure S1. 2. The variant NM_001164416.1:c.124C>T:p.(Arg42*) in 17DG0782 is now correctly listed under the name H2BFM in the abstract, Table 1, Table S1 and Table S2. 3. Nomenclature of MADD is changed to NM_001135943.1:c.2930T>G:p.(Leu977Arg) in 17DG0771 (From NM_001135943.1:c.2930T>G:p. (Val977Gly) in results, Table 1, Table S1, and Table S2. The authors sincerely apologize for these errors and appreciate the opportunity to mend the records