Recessive truncating NALCN mutation in infantile neuroaxonal dystrophy with facial dysmorphism

Background Infantile neuroaxonal dystrophy (INAD) is a recessive disease that results in total neurological degeneration and death in childhood. PLA2G6 mutation is the underlying genetic defect, but rare genetic heterogeneity has been demonstrated. One of the five families we studied did not link to PLA2G6 locus, and in the family one of the two affected siblings additionally had atypical features including facial dysmorphism, pectus carinatum, scoliosis, pes varus, zygodactyly and bilateral cryptorchidism as well as cerebellar atrophy, as previously reported. Methods Sural biopsy was investigated by electron microscopy. PLA2G6 was screened for mutations by Sanger sequencing. In the mutation-free family, candidate disease loci were found via linkage analysis using data from single nucleotide polymorphism genome scans. Exome sequencing was applied to find the variants at the loci. Results PLA2G6 mutations were identified in four families including the one with an unusually severe phenotype that led to death within the first 2 years of life. In the remaining family, seven candidate loci totalling 15.2 Mb were found and a homozygous truncating mutation p.Q642X was identified in NALCN at 13q32.3. The patients are around 20-years-old. Conclusions NALCN is the gene responsible for INAD with facial dysmorphism. The patients have lived to adulthood despite severe growth and neuromotor retardation. NALCN forms a voltage-independent ion channel with a role in the regulation of neuronal excitability. Our findings broaden the spectrum of genes associated with neuroaxonal dystrophy. Testing infants with idiopathic severe growth retardation and neurodegeneration for NALCN mutations could benefit families.