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Ann Clin Transl Neurol. 2016 Dec 20;4(1):26-35. doi: 10.1002/acn3.372. eCollection 2017 Jan.

Biallelic SCN10A mutations in neuromuscular disease and epileptic encephalopathy.

Author information

1
Pathology-Genetics Sidra Medical and Research Center Doha Qatar; Qatar Biomedical Research Institute Medical Genetics Center Hamad Bin Khalifa University Doha Qatar; Genetics Yale University School of Medicine New Haven Chicago.
2
Centre de Génétique Hôpital d'Enfant Dijon France.
3
Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda Maryland; Undiagnosed Diseases Program National Human Genome Research Institute National Institutes of Health Bethesda Maryland.
4
Pediatrics University of Iowa Iowa City Iowa.
5
Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda Maryland.
6
Clinical and Metabolic Genetics Pediatrics Hamad Medical Corporation Doha Qatar; Weill Cornell Medical College Doha Qatar.
7
Qatar Biomedical Research Institute Medical Genetics Center Hamad Bin Khalifa University Doha Qatar.
8
Human Genetics University of Chicago Chicago Illinois.
9
Undiagnosed Diseases Program National Human Genome Research Institute National Institutes of Health Bethesda Maryland.
10
Intramural Sequencing Center and Comparative Genomics Unit Genome Technology Branch National Genome Research Institute National Institutes of Health Bethesda Maryland.
11
Shafallah Medical Genetics Center Doha Qatar.
12
Qatar Biomedical Research Institute Medical Genetics Center Hamad Bin Khalifa University Doha Qatar; Pediatrics University of Iowa Iowa City Iowa; Pediatrics University of Jordan Amman Jordan.

Abstract

OBJECTIVES:

Two consanguineous families, one of Sudanese ethnicity presenting progressive neuromuscular disease, severe cognitive impairment, muscle weakness, upper motor neuron lesion, anhydrosis, facial dysmorphism, and recurrent seizures and the other of Egyptian ethnicity presenting with neonatal hypotonia, bradycardia, and recurrent seizures, were evaluated for the causative gene mutation.

METHODS AND RESULTS:

Homozygosity mapping and whole exome sequencing (WES) identified damaging homozygous variants in SCN10A, namely c.4514C>T; p.Thr1505Met in the first family and c.4735C>T; p.Arg1579* in the second family. A third family, of Western European descent, included a child with febrile infection-related epilepsy syndrome (FIRES) who also had compound heterozygous missense mutations in SCN10A, namely, c.3482T>C; p.Met1161Thr and c.4709C>A; p.Thr1570Lys. A search for SCN10A variants in three consortia datasets (EuroEPINOMICS, Epi4K/EPGP, Autism/dbGaP) identified an additional five individuals with compound heterozygous variants. A Hispanic male with infantile spasms [c.2842G>C; p.Val948Leu and c.1453C>T; p.Arg485Cys], and a Caucasian female with Lennox-Gastaut syndrome [c.1529C>T; p.Pro510Leu and c.4984G>A; p.Gly1662Ser] in the epilepsy databases and three in the autism databases with [c.4009T>A; p.Ser1337Thr and c.1141A>G; p.Ile381Val], [c.2972C>T; p.Pro991Leu and c.2470C>T; p.His824Tyr], and [c.4009T>A; p.Ser1337Thr and c.2052G>A; p.Met684Ile].

INTERPRETATION:

SCN10A is a member of the voltage-gated sodium channel (VGSC) gene family. Sodium channels are responsible for the instigation and proliferation of action potentials in central and peripheral nervous systems. Heterozygous mutations in VGSC genes cause a wide range of epileptic and peripheral nervous system disorders. This report presents autosomal recessive mutations in SCN10A that may be linked to epilepsy-related phenotypes, Lennox-Gastaut syndrome, infantile spasms, and Autism Spectrum Disorder.

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