TY - JOUR

T1 - A new neurodevelopmental disorder linked to heterozygous variants in UNC79

AU - Bayat, Allan

AU - Liu, Zhenjiang

AU - Luo, Sheng

AU - Fenger, Christina D.

AU - Højte, Anne F.

AU - Isidor, Bertrand

AU - Cogne, Benjamin

AU - Larson, Austin

AU - Zanus, Caterina

AU - Faletra, Flavio

AU - Keren, Boris

AU - Musante, Luciana

AU - Gourfinkel-An, Isabelle

AU - Perrine, Charles

AU - Demily, Caroline

AU - Lesca, Gaeton

AU - Liao, Weiping

AU - Ren, Dejian

N1 - Publisher Copyright: © 2023 American College of Medical Genetics and Genomics

PY - 2023

Y1 - 2023

N2 - Purpose: The “NALCN channelosome” is an ion channel complex that consists of multiple proteins, including NALCN, UNC79, UNC80, and FAM155A. Only a small number of individuals with a neurodevelopmental syndrome have been reported with disease causing variants in NALCN and UNC80. However, no pathogenic UNC79 variants have been reported, and in vivo function of UNC79 in humans is largely unknown. Methods: We used international gene-matching efforts to identify patients harboring ultrarare heterozygous loss-of-function UNC79 variants and no other putative responsible genes. We used genetic manipulations in Drosophila and mice to test potential causal relationships between UNC79 variants and the pathology. Results: We found 6 unrelated and affected patients with UNC79 variants. Five patients presented with overlapping neurodevelopmental features, including mild to moderate intellectual disability and a mild developmental delay, whereas a single patient reportedly had normal cognitive and motor development but was diagnosed with epilepsy and autistic features. All displayed behavioral issues and 4 patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function variant have a developmental delay in body weight compared with wild type. In addition, they have impaired ability in learning and memory. Conclusion: Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurologic pathologies.

AB - Purpose: The “NALCN channelosome” is an ion channel complex that consists of multiple proteins, including NALCN, UNC79, UNC80, and FAM155A. Only a small number of individuals with a neurodevelopmental syndrome have been reported with disease causing variants in NALCN and UNC80. However, no pathogenic UNC79 variants have been reported, and in vivo function of UNC79 in humans is largely unknown. Methods: We used international gene-matching efforts to identify patients harboring ultrarare heterozygous loss-of-function UNC79 variants and no other putative responsible genes. We used genetic manipulations in Drosophila and mice to test potential causal relationships between UNC79 variants and the pathology. Results: We found 6 unrelated and affected patients with UNC79 variants. Five patients presented with overlapping neurodevelopmental features, including mild to moderate intellectual disability and a mild developmental delay, whereas a single patient reportedly had normal cognitive and motor development but was diagnosed with epilepsy and autistic features. All displayed behavioral issues and 4 patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function variant have a developmental delay in body weight compared with wild type. In addition, they have impaired ability in learning and memory. Conclusion: Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurologic pathologies.

KW - Developmental delay

KW - Epilepsy

KW - Genetics

KW - Intellectual disability

KW - Neurology

U2 - 10.1016/j.gim.2023.100894

DO - 10.1016/j.gim.2023.100894

M3 - Journal article

C2 - 37183800

AN - SCOPUS:85162935113

VL - 25

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 9

M1 - 100894

ER -