UNC80 – Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies 2

UNC80 encodes a large cytoplasmic protein essential for the stability and function of the NALCN sodium‐leak channel complex. Biallelic loss‐of‐function variants in UNC80 underlie autosomal recessive infantile hypotonia with psychomotor retardation and characteristic facies 2 (IHPRF2), an early‐onset neurodevelopmental disorder characterized by profound hypotonia, global developmental delay, intellectual disability, variable seizures, growth retardation and distinctive facial features (MONDO:0014777).

Two unrelated Chinese patients presented with compound heterozygous UNC80 variants detected by WES: c.3719G>A (p.Trp1240Ter)/c.4926_4937del (p.Asn1643_Leu1646del) in patient 1 and c.4963C>T (p.Arg1655Cys)/c.8385C>G (p.Tyr2795Ter) in patient 2, with concordant DD/ID and hypotonia but variable epilepsy, hyperactivity and growth outcomes (PMID:29572195).

In three consanguineous Saudi Arabian families and one Egyptian family, recessive UNC80 mutations including two apparent loss‐of‐function alleles were identified in individuals with infantile encephalopathy, severe hypotonia, normal brain MRI and developmental impairment. These cases expand the phenotypic spectrum of IHPRF2 and underscore genetic heterogeneity in Middle Eastern populations (PMID:26708753).

Homozygosity mapping in Bedouin Israeli families localized IHPRF2 to a 7.5 Mb locus on chromosome 2, with a homozygous nonsense variant c.151C>T (p.Arg51Ter) segregating with disease and absent in 150 ethnically matched controls, confirming a loss‐of‐function mechanism (PMID:26545877).

Overall, at least six unrelated probands with biallelic UNC80 variants (four families) and segregation of homozygous or compound heterozygous alleles support a definitive autosomal recessive inheritance. The variant spectrum comprises nonsense, frameshift, splice-site, small in‐frame deletion and missense alleles, with recurrent LoF alleles across populations.

Functional studies demonstrate that UNC80 is required to bridge NALCN to UNC79 within the channelosome; truncating UNC80 alleles destabilize the complex and abolish neuronal Na⁺ leak conductance, consistent with a loss‐of‐function pathogenic mechanism ([PMID:26708753]).

Key Take-home: Biallelic UNC80 loss-of-function variants cause IHPRF2 via a recessive haploinsufficiency mechanism, with robust genetic and experimental concordance that informs diagnosis, genetic counseling and variant interpretation.

References

• Gene | 2018 | Biallelic UNC80 mutations caused infantile hypotonia with psychomotor retardation and characteristic facies 2 in two Chinese patients with variable phenotypes. PMID:29572195
• American Journal of Human Genetics | 2016 | Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy. PMID:26708753
• Journal of Medical Genetics | 2016 | UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN. PMID:26545877

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