Diverse clinical presentation of SPTBN1 variants: Complex versus primary attention-deficit/hyperactivity disorder.

Autor: O'Connell M; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Division of Genetics & Genomics, Boston Children's Hospital, Boston, Massachusetts, USA., Harstad E; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Division of Developmental Medicine, Boston Children's Hospital, Boston, Massachusetts, USA., Aites J; Division of Developmental Medicine, Boston Children's Hospital, Boston, Massachusetts, USA., Hayes K; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Division of Genetics & Genomics, Boston Children's Hospital, Boston, Massachusetts, USA., Arnett AB; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Division of Developmental Medicine, Boston Children's Hospital, Boston, Massachusetts, USA., Scotellaro J; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Division of Genetics & Genomics, Boston Children's Hospital, Boston, Massachusetts, USA., Patel S; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Division of Genetics & Genomics, Boston Children's Hospital, Boston, Massachusetts, USA., Brewster SJ; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Division of Genetics & Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.; Division of Developmental Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, Massachusetts, USA., Barbaresi W; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Division of Developmental Medicine, Boston Children's Hospital, Boston, Massachusetts, USA., Doan RN; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Division of Genetics & Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2025 Jan; Vol. 197 (1), pp. e63851. Date of Electronic Publication: 2024 Aug 20.
DOI: 10.1002/ajmg.a.63851
Abstrakt: Attention-deficit/hyperactivity disorder (ADHD) belongs to a phenotypically broad class of mental health disorders impacting social and cognitive functioning. Despite heritability estimates of 77%-88% and a global prevalence of up to 1 in 20 children, most of the underlying genetic etiology of the disorder remains undiscovered, making it challenging to obtain a clinical molecular genetic diagnosis and to develop new treatments (Biological Psychiatry, 2005, 57, 1313; Psychological Bulletin, 2009, 135, 608; Psychological Medicine, 2014, 44, 2223). Here we report the identification of a novel ultra-rare heterozygous loss-of-function (p.Q1625*) variant in a child with complex ADHD (i.e., comorbid mild intellectual disability [ID]) and a missense (p.G1748R) variant (allele frequency of 4.7 × 10 -5 ) in a child with primary ADHD (i.e., absence of comorbid autism spectrum disorder [ASD], ID, or syndromic features) both in the SPTBN1 gene. Missense variants in SPTBN1 have been reported in individuals with developmental disorders, language and communication disorders, and motor delays in recent publications (Nature Genetics, 2021, 53, 1006; American Journal of Medical Genetics Part A, 2021, 185, 2037) and ClinVar, though most variants in ClinVar have uncertain disease associations. The functional impact of these 135 variants, including from the current study, were further assessed using prediction scores from the recently developed AlphaMissense tool and benchmarked against published functional studies on a subset of the variants. While heterozygous SPTBN1 variants have recently been associated with neurodevelopmental disorders characterized by global developmental delay, intellectual disability, and behavioral abnormalities, the two patients in the current study expand the phenotypic spectrum to include ADHD in the absence of more severe neurodevelopmental disorders, such as ASD and moderate to severe ID. Furthermore, the culmination of these data with existing reported cases suggests that variation including loss of function and missense events underlie a broader clinical spectrum than previously understood.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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