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.
The ornithine decarboxylase 1 (ODC1) gene plays an important role in physiological and cell developmental processes including embryogenesis, organogenesis, and neoplastic cell growth. Here, we report an 32‐month‐old Caucasian female with a heterozygous de novo nonsense mutation in the ODC1 gene that leads to a premature abrogation of 14‐aa residues at the ODC protein c‐terminus. This is the first human case confirming similar symptoms observed in a transgenic ODC1 mouse model first described over 20 years ago. Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss. We here describe for the first time a new pediatric disorder that is directly linked to a de novo pathogenic variant in the ODC1 gene. The ODC1 gene mutation (c.1342 A>T) was identified by whole‐exome sequencing and confirmed by Sanger sequencing. Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls. Our autosomal dominant patient who carries this gain‐of‐function ODC1 mutation may benefit from treatment with α‐difluoromethylornithine, a well‐tolerated, U.S. Food and Drug Administration (FDA). FDA‐approved drug.
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