Heterozygous variants in SPTBN1 cause intellectual disability and autism.

Autor: Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Xiao R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics Laboratories, Houston, Texas, USA., Bekheirnia MR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA., Kanani F; Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK., Parker MJ; Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK., Koenig MK; Department of Pediatrics, University of Texas McGovern Medical School, Houston, Texas, USA., van Haeringen A; Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands., Ruivenkamp C; Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands., Rosmaninho-Salgado J; Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal., Almeida PM; Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal., Sá J; Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal., Pinto Basto J; Molecular Diagnostics and Clinical Genomics, CGC Genetics, Porto, Portugal., Palen E; Autism & Developmental Medicine Institute, Geisinger, Danville, Pennsylvania, USA., Oetjens KF; Autism & Developmental Medicine Institute, Geisinger, Danville, Pennsylvania, USA., Burrage LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA., Xia F; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics Laboratories, Houston, Texas, USA., Liu P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics Laboratories, Houston, Texas, USA., Eng CM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics Laboratories, Houston, Texas, USA., Yang Y; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics Laboratories, Houston, Texas, USA., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Lee BH; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2021 Jul; Vol. 185 (7), pp. 2037-2045. Date of Electronic Publication: 2021 Apr 13.
DOI: 10.1002/ajmg.a.62201
Abstrakt: Spectrins are common components of cytoskeletons, binding to cytoskeletal elements and the plasma membrane, allowing proper localization of essential membrane proteins, signal transduction, and cellular scaffolding. Spectrins are assembled from α and β subunits, encoded by SPTA1 and SPTAN1 (α) and SPTB, SPTBN1, SPTBN2, SPTBN4, and SPTBN5 (β). Pathogenic variants in various spectrin genes are associated with erythroid cell disorders (SPTA1, SPTB) and neurologic disorders (SPTAN1, SPTBN2, and SPTBN4), but no phenotypes have been definitively associated with variants in SPTBN1 or SPTBN5. Through exome sequencing and case matching, we identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities). Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset. Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis. Our findings support the essential roles of SPTBN1 in human neurodevelopment and expand the knowledge of human spectrinopathy disorders.
(© 2021 Wiley Periodicals LLC.)
Databáze: MEDLINE
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