Dataset Information

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

ABSTRACT: SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system.

SUBMITTER: Cousin MA

PROVIDER: S-EPMC8273149 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

Cousin Margot A MA Creighton Blake A BA Breau Keith A KA Spillmann Rebecca C RC Torti Erin E Dontu Sruthi S Tripathi Swarnendu S Ajit Deepa D Edwards Reginald J RJ Afriyie Simone S Bay Julia C JC Harper Kathryn M KM Beltran Alvaro A AA Munoz Lorena J LJ Falcon Rodriguez Liset L Stankewich Michael C MC Person Richard E RE Si Yue Y Normand Elizabeth A EA Blevins Amy A May Alison S AS Bier Louise L Aggarwal Vimla V Mancini Grazia M S GMS van Slegtenhorst Marjon A MA Cremer Kirsten K Becker Jessica J Engels Hartmut H Aretz Stefan S MacKenzie Jennifer J JJ Brilstra Eva E van Gassen Koen L I KLI van Jaarsveld Richard H RH Oegema Renske R Parsons Gretchen M GM Mark Paul P Helbig Ingo I McKeown Sarah E SE Stratton Robert R Cogne Benjamin B Isidor Bertrand B Cacheiro Pilar P Smedley Damian D Firth Helen V HV Bierhals Tatjana T Kloth Katja K Weiss Deike D Fairley Cecilia C Shieh Joseph T JT Kritzer Amy A Jayakar Parul P Kurtz-Nelson Evangeline E Bernier Raphael A RA Wang Tianyun T Eichler Evan E EE van de Laar Ingrid M B H IMBH McConkie-Rosell Allyn A McDonald Marie T MT Kemppainen Jennifer J Lanpher Brendan C BC Schultz-Rogers Laura E LE Gunderson Lauren B LB Pichurin Pavel N PN Yoon Grace G Zech Michael M Jech Robert R Winkelmann Juliane J Beltran Adriana S AS Zimmermann Michael T MT Temple Brenda B Moy Sheryl S SS Klee Eric W EW Tan Queenie K-G QK Lorenzo Damaris N DN

Nature genetics 20210701 7

SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify ...[more]

PMID: 34211179

Similar Datasets

Project description:BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, characterized by development and enlargement of kidney cysts, eventually leading to end-stage kidney disease (ESKD). Pathogenic variants in the PKD1 and PKD2 genes are the major cause of ADPKD; additional rare variants in the GANAB, DNAJB11, ALG5 and ALG9 genes have been found in a minority of ADPKD patients. More recently, a significant number of ADPKD families have been linked to monoallelic variants in the IFT140 gene.MethodsIn this retrospective study, we tested the prevalence of the known causative genes of ADPKD-spectrum phenotype, including the PKD1, PKD2, GANAB, DNAJB11, ALG5, ALG and IFT140 genes, in a cohort of 129 ADPKD patients who consecutively underwent genetic testing in a single centre in Italy. Genetic testing utilized a combination of targeted next-generation sequencing, long-range polymerase chain reaction, Sanger sequencing and multiplex ligation-dependent probe amplification. Clinical evaluation was conducted through renal function testing and imaging features, including ultrasonography, computer tomography and magnetic resonance imaging.ResultsOf the 129 enrolled patients, 86 (66.7%) had pathogenic variants in PKD1 and 28 (21.7%) in PKD2, loss of function pathogenic variants in the IFT140 gene were found in 3 unrelated patients (2.3%), no pathogenic variants were found in other ADPKD genes and 12 patients (9.3%) remained genetically unresolved (ADPKD-GUR). Familial clinical and genetic screening of the index patients with ADPKD due to an IFT140 pathogenic variant (ADPKD-IFT140) allowed identification of eight additional affected relatives. In the 11 ADPKD-IFT140 patients, the renal phenotype was characterized by mild and late-onset PKD, with large renal cysts and limited kidney insufficiency. Extrarenal manifestations, including liver cysts, were rarely seen.ConclusionOur data suggest the monoallelic pathogenic IFT140 variants are the third most common cause of the ADPKD-spectrum phenotype in Italy, usually associated with a mild and atypical renal cystic disease.

Dataset Information

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

Publications

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets