Mutations in NALCN cause an autosomal-recessive syndrome with severe hypotonia, speech impairment, and cognitive delay.
Sodium leak channel, nonselective (NALCN) is a voltage-independent and cation-nonselective channel that is mainly responsible for the leaky sodium transport across neuronal membranes and controls neuronal excitability. Although NALCN variants have been conflictingly reported to be in linkage disequilibrium with schizophrenia and bipolar disorder, to our knowledge, no mutations have been reported to date for any inherited disorders. Using linkage, SNP-based homozygosity mapping, targeted sequencing, and confirmatory exome sequencing, we identified two mutations, one missense and one nonsense, in NALCN in two unrelated families. The mutations cause an autosomal-recessive syndrome characterized by subtle facial dysmorphism, variable degrees of hypotonia, speech impairment, chronic constipation, and intellectual disability. Furthermore, one of the families pursued preimplantation genetic diagnosis on the basis of the results from this study, and the mother recently delivered healthy twins, a boy and a girl, with no symptoms of hypotonia, which was present in all the affected children at birth. Hence, the two families we describe here represent instances of loss of function in human NALCN.
Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Moeenaldeen D
MD
Al-Sayed
Hamad
H
Al-Zaidan
Albandary
A
Albakheet
Hana
H
Hakami
Rosan
R
Kenana
Yusra
Y
Al-Yafee
Mazhor
M
Al-Dosary
Alya
A
Qari
Tarfa
T
Al-Sheddi
Muhammed
M
Al-Muheiza
Wafa
W
Al-Qubbaj
Yamina
Y
Lakmache
Hindi
H
Al-Hindi
Muhammad
M
Ghaziuddin
Dilek
D
Colak
Namik
N
Kaya
D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D019465:Craniofacial Abnormalities; D059472:Exome; D019066:Facies; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins; D009123:Muscle Hypotonia / Q000235:genetics*; D009133:Muscular Atrophy / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D015222:Sodium Channels / Q000235:genetics*; D013064:Speech Disorders / Q000235:genetics*
D018389:Codon, Nonsense; D007473:Ion Channels; D008565:Membrane Proteins; C544681:NALCN protein, human; D015222:Sodium Channels