Sabina Barresi1, Maria Lisa Dentici2, Francesca Manzoni3, Emanuele Bellacchio2, Emanuele Agolini2, Simone Pizzi2, Andrea Ciolfi2, Mark Tarnopolsky4, Lauren Brady4, Giacomo Garone5, Antonio Novelli2, Davide Mei6, Renzo Guerrini6, Alessandro Capuano5, Chiara Pantaleoni3, Marco Tartaglia2. 1. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy. Electronic address: sabina.barresi@opbg.net. 2. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy. 3. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 4. Division of Neuromuscular and Neurometabolic Diseases, Department of Pediatrics, McMaster University Medical Center, Ontario, Canada. 5. Department of Neurosciences, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy. 6. Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
Abstract
BACKGROUND: Congenital ataxias associated with cerebellar atrophy are clinically heterogeneous conditions with a variable age of onset and a diverse molecular basis. The hypothesis-free approach of genomic sequencing has led to the discovery of new genes implicated in these disorders and the identification of unexpected genotype-phenotype correlations. Although a recurrent heterozygous mutation (p.Arg1715His) in CACNA1G is known to cause adult-onset spinocerebellar ataxia 42 (SCA42*616795), gain-of-function mutations in this gene have recently been identified by whole exome sequencing (WES) in four children with cerebellar atrophy and ataxia, psychomotor delay, and other variable features. METHODS: We describe four children from unrelated families with cerebellar anomalies on magnetic resonance imaging (atrophy or hypoplasia of the cerebellar vermis), hypertonia, psychomotor and speech delay, severe intellectual disability, ophthalmologic features and peculiar dysmorphic traits. All patients underwent a trio-based WES analysis. Clinical records were used to characterize the clinical profile of this newly recognized disorder. RESULTS: Two previously reported de novo disease-causing mutations in CACNA1G (c.2881G>A, p.Ala961Thr and c.4591A>G, p.Met1531Val) were identified in these patients, providing further evidence of the specific impact of these variants. All four patients exhibit distinctive dysmorphic and ectodermal features which overlap those of the previously reported patients, allowing us to define the major features characterizing this homogeneous neurodevelopmental syndromic disorder associated with upregulated CACNA1G function. CONCLUSION: Our findings confirm the specific association between a narrow spectrum of missense mutations in CACNA1G and a novel syndrome with infantile-onset cerebellar ataxiaand provide a dysmorphologic delineation of this novel neurodevelopmental trait.
BACKGROUND:Congenital ataxias associated with cerebellar atrophy are clinically heterogeneous conditions with a variable age of onset and a diverse molecular basis. The hypothesis-free approach of genomic sequencing has led to the discovery of new genes implicated in these disorders and the identification of unexpected genotype-phenotype correlations. Although a recurrent heterozygous mutation (p.Arg1715His) in CACNA1G is known to cause adult-onset spinocerebellar ataxia 42 (SCA42*616795), gain-of-function mutations in this gene have recently been identified by whole exome sequencing (WES) in four children with cerebellar atrophy and ataxia, psychomotor delay, and other variable features. METHODS: We describe four children from unrelated families with cerebellar anomalies on magnetic resonance imaging (atrophy or hypoplasia of the cerebellar vermis), hypertonia, psychomotor and speech delay, severe intellectual disability, ophthalmologic features and peculiar dysmorphic traits. All patients underwent a trio-based WES analysis. Clinical records were used to characterize the clinical profile of this newly recognized disorder. RESULTS: Two previously reported de novo disease-causing mutations in CACNA1G (c.2881G>A, p.Ala961Thr and c.4591A>G, p.Met1531Val) were identified in these patients, providing further evidence of the specific impact of these variants. All four patients exhibit distinctive dysmorphic and ectodermal features which overlap those of the previously reported patients, allowing us to define the major features characterizing this homogeneous neurodevelopmental syndromic disorder associated with upregulated CACNA1G function. CONCLUSION: Our findings confirm the specific association between a narrow spectrum of missense mutations in CACNA1G and a novel syndrome with infantile-onset cerebellar ataxiaand provide a dysmorphologic delineation of this novel neurodevelopmental trait.
Authors: Yan-Ling Zhang; Sean P Moran; Andrew Allen; David Baez-Nieto; Qihong Xu; Lei A Wang; William E Martenis; Joshua R Sacher; Jennifer P Gale; Michel Weïwer; Florence F Wagner; Jen Q Pan Journal: ACS Pharmacol Transl Sci Date: 2022-02-25
Authors: Benjamin S O'Brien; Rebekah L Mokry; Megan L Schumacher; Kirthi Pulakanti; Sridhar Rao; Scott S Terhune; Allison D Ebert Journal: iScience Date: 2022-03-17