A Homozygous Truncating Mutation in NALCN Causing IHPRF1: Detailed Clinical Manifestations and a Review of Literature

Abstract

Infantile hypotonia, with psychomotor retardation and characteristic facies 1 (IHPRF1), is a rare disorder characterized by global developmental delay and dysmorphic features. This syndrome is caused by genetic anomalies within the NALCN gene. The current report examines a 9-year-old female IHPRF1 patient. Our objective was to contribute to the delineation of the underlying factors influencing this rare condition. Whole exome sequencing (WES) was utilized to identify the disease-causing mutation in the affected individual. Subsequently, Sanger sequencing was performed for the patient, her parents, and two close relatives in order to confirm the detected mutation. Moreover, detailed clinical examinations including EEG, echocardiography, and biochemical/physical tests were carried out to elucidate the effects of the mutation. WES identified a homozygous nonsense mutation in the NALCN gene (c.2563C>T p.R855X). This mutation was confirmed by Sanger sequencing in the patient and her family members and segregated with the autosomal recessive inheritance pattern of IHPRF1. Moreover, genotype-phenotype correlation analysis confirmed the disease-causing nature of this mutation. The current report provides the first detailed description of a patient with this homozygous nonsense mutation (c.2563C>T p.R855X) and expands the clinical spectrum of IHPRF1 disease. Possible influences of sex and other factors on this disease are discussed and a review of the literature is also provided.

Keywords:

• global developmental delay
• dysmorphism
• intellectual disability
• motor retardation
• cognitive delay

Abbreviations

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ASD, atrial septal defect; CLIFAHDD, congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome; EEG, electroencephalography; IHPRF, infantile hypotonia with psychomotor retardation and characteristic facies; NALCN, sodium leak channel, non-selective; NMD, nonsense-mediated decay; QF-PCR, quantitative fluorescence polymerase chain reaction; STR, short tandem repeats; SP, substance P; TR, tricuspid regurgitation; WES, whole exome sequencing.

Ethics Approval

This study was conducted under the approval of the ethics committee of Semnan University of medical sciences, Semnan, Iran. Written informed consent was obtained from the legal guardians prior to all the relevant clinical tests and the preparation and submission of the manuscript. Consent for publication of patient’s data and any identifiable features is also available.

Acknowledgments

The authors express their sincere gratitude to the patient and her respected family who kindly consented to join the present study. We would like to thank Dr. Nooshin Masoudian (Department of Internal Medicine, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran) and Dr. Samira Mehralizade (Semnan University of Medical Sciences, Semnan, Iran) for their technical collaborations, as well.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest for this work.

Additional information

Funding

No funding was obtained for this study.