title: Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population.
abstract: Cerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are highly heterogeneous on both the genetic and clinical levels. Patients with these signs also typically present with non-specific neuroimaging results that can help prioritize further investigation but don't suggest a specific molecular diagnosis.
  
  
  
  To genetically explore a cohort of 18 Egyptian families with undiagnosed cerebellar atrophy identified on MRI, we sequenced probands and some non-affected family members via high-coverage whole exome sequencing (WES; >97 % of the exome covered at least by 30x). Patients were mostly from consanguineous families, either sporadic or multiplex. We analyzed WES data and filtered variants according to dominant and recessive inheritance models.
  
  
  
  We successfully identified disease-causing mutations in half of the families screened (9/18). These mutations are located in seven different genes, PLA2G6 being the gene most frequently mutated (n = 3). We also identified a recurrent de novo mutation in the KIF1A gene and a molybdenum cofactor deficiency caused by the loss of the start codon in the MOCS2A open-reading frame in a mildly affected subject.
  
  
  
  This study illustrates the necessity of screening for dominant mutations in WES data from consanguineous families. Our identification of a patient with a mild and improving phenotype carrying a previously characterized severe loss of function mutation also broadens the clinical spectrum associated with molybdenum cofactor deficiency.
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo, 12311, Egypt.
authors.forename: Hisham
authors.initials: H
authors.lastname: Megahed
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris, France.|Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Michaël
authors.initials: M
authors.lastname: Nicouleau
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris, France.|Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.|Department of Genetics, Necker Enfants Malades University Hospital, APHP, 75015, Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Barcia
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris, France.|Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Medina-Cano
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris, France.|Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Siquier-Pernet
authors.affiliation: Genomic Platform, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Citée University, Imagine Institute, 75015, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Genomic Platform, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Citée University, Imagine Institute, 75015, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Parisot
authors.affiliation: Bioinformatic Platform, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Citée University, Imagine Institute, 75015, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Masson
authors.affiliation: Bioinformatic Platform, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Citée University, Imagine Institute, 75015, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.affiliation: Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.|Imagine Institute, INSERM UMR 1163, Genetics of mitochondrial diseases, 75015, Paris, France.|Department of Genetics, Necker Enfants Malades University Hospital, APHP, 75015, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.|Imagine Institute, INSERM UMR 1163, Embryology and genetics of human malformation, 75015, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.affiliation: Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.|Pediatric Neurology, Necker Enfants Malades University Hospital, APHP, 75015, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.affiliation: Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.|Department of Genetics, Necker Enfants Malades University Hospital, APHP, 75015, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.|Department of Pediatric Radiology, Necker Enfants Malades University Hospital, APHP, 75015, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris, France.|Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris, France. vincent.cantagrel@inserm.fr.|Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France. vincent.cantagrel@inserm.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cantagrel
mesh_terms: D001284:Atrophy / Q000175:diagnosis* / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002524:Cerebellar Ataxia / Q000175:diagnosis / Q000235:genetics; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics*; D042241:Early Diagnosis; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods*
keywords: Cerebellum atrophy; Exome sequencing; Intellectual disability; KIF1A; MOCS2; Molybdenum cofactor deficiency