Identification of a novel homozygous UNC80 variant in a child with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2)
The UNC80 gene encodes for a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. In this study, we report on a novel homozygous mutation in UNC80 in a Palestinian-Emirati patient suffering infantile hypotonia with psychomotor retardation and characteristic facies. This mutation was detected by whole exome sequencing and confirmed using Sanger sequencing in the patient-parents trio. Numerous elements in the patient’s phenotype were in agreement with the few reported cases of UNC80 mutations; however there are some notable differences. We present comprehensive clinical and molecular accounts of this mutation in addition to a full review of previously reported patients of UNC80 mutations.
KeywordsPsychomotor retardation Intellectual disability Epilepsy UNC80 gene Novel mutation Emirati
Authors would like to thank the patient and his family for full cooperation. Thanks also go to Dubai Health Authority and Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences for continuous and comprehensive support.
Compliance with ethical standards
Conflicts of interest
This study was granted ethical approval for full compliance with the Code of Ethics of the Dubai Health Authority in the United Arab Emirates. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The guardian (parent) of the patient consented to both participation and publication of the case.
- Humphrey JA, Hamming KS, Thacker CM, Scott RL, Sedensky MM, Snutch TP, Morgan PG, Nash HA (2007) A putative cation channel and its novel regulator: cross-species conservation of effects on general anesthesia. Curr Biol 17:624–629. https://doi.org/10.1016/j.cub.2007.02.037 CrossRefPubMedGoogle Scholar
- Lear BC, Darrah EJ, Aldrich BT, Gebre S, Scott RL, Nash HA, Allada R (2013) UNC79 and UNC80, putative auxiliary subunits of the NARROW ABDOMEN ion channel, are indispensable for robust circadian locomotor rhythms in Drosophila. PLoS One 8:e78147. https://doi.org/10.1371/journal.pone.0078147 CrossRefPubMedPubMedCentralGoogle Scholar
- Perez Y, Kadir R, Volodarsky M, Noyman I, Flusser H, Shorer Z, Gradstein L, Birnbaum RY, Birk OS (2015) UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN. J Med Genet 53:397–402. https://doi.org/10.1136/jmedgenet-2015-103352 CrossRefPubMedGoogle Scholar
- Shamseldin HE, Faqeih E, Alasmari A, Zaki MS, Gleeson JG, Alkuraya FS (2016) Mutations in UNC80, encoding part of the UNC79-UNC80-NALCN Channel complex, cause autosomal-recessive severe infantile encephalopathy. Am J Hum Genet 98:210–215. https://doi.org/10.1016/j.ajhg.2015.11.013 CrossRefPubMedGoogle Scholar
- Stray-Pedersen A, Cobben JM, Prescott TE, Lee S, Cang C, Aranda K, Ahmed S, Alders M, Gerstner T, Aslaksen K, Tetreault M, Qin W, Hartley T, Jhangiani SN, Muzny DM, Tarailo-Graovac M, van Karnebeek CD, Care4Rare Canada C, Baylor-Hopkins Center for Mendelian G, Lupski JR, Ren D, Yoon G (2016) Biallelic mutations in UNC80 cause persistent hypotonia, encephalopathy, growth retardation, and severe intellectual disability. Am J Hum Genet 98:202–209. https://doi.org/10.1016/j.ajhg.2015.11.004 CrossRefPubMedGoogle Scholar
- Valkanas E, Schaffer K, Dunham C, Maduro V, du Souich C, Rupps R, Adams DR, Baradaran-Heravi A, Flynn E, Malicdan MC, Gahl WA, Toro C, Boerkoel CF (2016) Phenotypic evolution of UNC80 loss of function. Am J Med Genet A 170:3106–3114. https://doi.org/10.1002/ajmg.a.37929 CrossRefPubMedPubMedCentralGoogle Scholar
- Yeh E, Ng S, Zhang M, Bouhours M, Wang Y, Wang M, Hung W, Aoyagi K, Melnik-Martinez K, Li M, Liu F, Schafer WR, Zhen M (2008) A putative cation channel, NCA-1, and a novel protein, UNC-80, transmit neuronal activity in C. elegans. PLoS Biol 6:e55. https://doi.org/10.1371/journal.pbio.0060055 CrossRefPubMedPubMedCentralGoogle Scholar