Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1.
Toshiki TakenouchiMie InabaTomoko UeharaTakao TakahashiKenjiro KosakiSeiji MizunoPublished in: American journal of medical genetics. Part A (2017)
Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.
Keyphrases
- early onset
- intellectual disability
- case report
- copy number
- autism spectrum disorder
- late onset
- end stage renal disease
- high resolution
- preterm infants
- ejection fraction
- chronic kidney disease
- electronic health record
- density functional theory
- sleep quality
- healthcare
- mitochondrial dna
- transcranial direct current stimulation
- depressive symptoms
- neural network
- working memory
- birth weight
- gestational age