title: A novel homozygous splice site mutation in NALCN identified in siblings with cachexia, strabismus, severe intellectual disability, epilepsy and abnormal respiratory rhythm.
abstract: We studied three siblings, born to consanguineous parents who presented with severe intellectual disability, cachexia, strabismus, seizures and episodes of abnormal respiratory rhythm. Whole exome sequencing led to identification of a novel homozygous splice site mutation, IVS29-1G > A in the NALCN gene, that resulted in aberrant transcript in the patients. NALCN encodes a voltage-independent cation channel, involved in regulation of neuronal excitability. Three homozygous mutations in the NALCN gene were previously identified in only eight patients with severe hypotonia, speech impairment, cognitive delay, constipation and Infantile-Neuroaxonal-dystrophy- like symptoms. Our patients broaden the clinical spectrum associated with recessive mutations in NALCN, featuring also disrupted respiratory rhythm mimicking homozygous Nalcn knockout mice.
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan Israel. Electronic address: morangal30@gmail.com.
authors.forename: Moran
authors.initials: M
authors.lastname: Gal
authors.affiliation: Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel; Laboratory of Molecular Medicine, Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Daniella
authors.initials: D
authors.lastname: Magen
authors.affiliation: Department of Pediatric Medicine, Clalit Health Services, Ibillin, Israel.
authors.forename: Younan
authors.initials: Y
authors.lastname: Zahran
authors.affiliation: Pediatric Neurology Unit and Epilepsy Service, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel. Electronic address: s_ravid@rambam.health.gov.il.
authors.forename: Sarit
authors.initials: S
authors.lastname: Ravid
authors.affiliation: Department of Radiology, Health Care Campus, Haifa, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Eran
authors.affiliation: The Genetic Institute, Emek Medical Center, Afula, Israel.
authors.forename: Morad
authors.initials: M
authors.lastname: Khayat
authors.affiliation: The Genetic Institute, Emek Medical Center, Afula, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Gafni
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan Israel.
authors.forename: Erez Y
authors.initials: EY
authors.lastname: Levanon
authors.affiliation: Metabolic Unit, Rambam Health Care Center, Haifa, Israel; Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
mesh_terms: D000818:Animals; D002100:Cachexia / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000235:genetics / Q000473:pathology; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D012640:Seizures / Q000235:genetics* / Q000473:pathology; D035781:Siblings; D015222:Sodium Channels / Q000235:genetics*; D013285:Strabismus / Q000235:genetics / Q000473:pathology
chemical_list: D007473:Ion Channels; D008565:Membrane Proteins; C544681:NALCN protein, human; D022821:RNA Splice Sites; D015222:Sodium Channels
keywords: Abnormal respiratory rhythm; Cachexia; Intellectual disability; NALCN gene; Seizures