Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy

Abstract

Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex.

Figure 1

Characterization of Four Families with Severe Non-Epileptic Encephalopathy (A) Pedigrees of the four study families. (B1) Facial image of individual F1_IV:5 (6 years and 5 months), showing high forehead, prominent nasal bridge, and tented upper lip. (B2) Facial image of individual F2_IV:1 (2 years). (B3) Facial image of individual F2_IV:2 (11 months). (B4) Facial image of individual F3_IV4 (8 years and 9 months), showing similar facial appearance to the other affected individuals. Note the additional presence of microcephaly, plagiocephaly, and brachycephaly. (B5) Facial images of individual F4_V:1 and (B6) of individual F4_V:2, showing similar but milder facial features. (B7 and B8) Brain MRI of individual F1_IV:5, showing mild diffuse brain atrophy.

Figure 2

Identification of UNC80 Mutations in Severe Non-Epileptic Encephalopathy (A) Genome-wide autozygosity mapping combining families 1, 2, and 3 reveals a single interval that is exclusively shared by the affected members and is demarcated by three navy bars (red arrow). (B) Linkage analysis shows a corresponding significant peak on chromosome 2. (C) Cartoon of UNC80 with the position of the two homozygous nonsense and one homozygous missense variants shown (in each chromatogram, the tracing of the affected individual is shown on top and that of the carrier parent is shown below with a red asterisk indicating the position of the variant).