Abstract
Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by retinitis pigmentosa (RP), truncal obesity, cognitive impairment, hypogonadism in men, polydactyly, and renal abnormalities with severe renal dysfunction. Twenty-two causative genes have already been reported for this disorder. In this study, we identified two unrelated Japanese patients with clinical diagnoses of BBS associated with compound heterozygous SCLT1 mutation. Patient 1 was a 10-year-old girl, and patient 2 was a 22-year-old man. Both the patients showed severe renal dysfunction in childhood, RP, mild intellectual disability, short stature, and truncal obesity, without oral aberrations and polydactyly. Patient 2 also had hypogonadism. We identified two missense variants in SCLT1, c.[1218G > A] and [1631A > G], in both the patients by next-generation sequencing. Subsequent cDNA analysis revealed that c.1218G > A affected exon 14 skipping in SCLT1. To date, SCLT1 has been reported as the causative gene of oral–facial–digital syndrome type IX, and Senior–Løken syndrome. The phenotypes of both the present patients were compatible with BBS. These results highlight SCLT1 as an additional candidate for BBS phenotype in an autosomal recessive manner.
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References
Forsythe E, Beales PL. Bardet-Biedl Syndrome. In: Adam MP, Ardinger HH, Pagon RA, editors. GeneReviews®. Seattle: University of Washington; 2003. p. 1993–2019.
Forsythe E, Kenny J, Bacchelli C, Beales PL. Managing Bardet-Biedl syndrome-now and in the future. Front Pediatr. 2018;6:23.
Feather SA, Woolf AS, Donnai D, Malcolm S, Winter RM. The oral-facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney disease and associated malformations, maps to Xp22.2-Xp22.3. Hum Mol Genet. 1997;6(7):1163–7.
Sakakibara N, Morisada N, Nozu K, Nagatani K, Ohta T, Shimizu J, et al. Clinical spectrum of male patients with OFD1 mutations. J Hum Genet. 2019;64(1):3–9.
Adly N, Alhashem A, Ammari A, Alkuraya FS. Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX. Hum Mutat. 2014;35(1):36–40.
Katagiri S, Hayashi T, Yoshitake K, Murai N, Matsui Z, Kubo H, et al. Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Løken syndrome. Sci Rep. 2018;8(1):16733.
Liu C, Cummins TR, Tyrrell L, Black JA, Waxman SG, Dib-Hajj SD. CAP-1A is a novel linker that binds clathrin and the voltage-gated sodium channel Na(v)1.8. Mol Cell Neurosci. 2005;28(4):636–49.
Tanos BE, Yang HJ, Soni R, Wang WJ, Macaluso FP, Asara JM, et al. Centriole distal appendages promote membrane docking, leading to cilia initiation. Genes Dev. 2013;27(2):163–8.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, On behalf of the ACMG Laboratory Quality Assurance Committee, et al. Standards and guidelines for the interpretation of sequence variants: a Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.
Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47(D1):D886–D89494.
Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PLoS ONE. 2012;7(10):e46688.
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073–81.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9.
Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. Mutation Taster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7(8):575–6.
Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol. 2010;6(12):e1001025.
Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010;20(1):110–21.
Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37(9):e67.
Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999;36(6):437–46.
Braun DA, Hildebrandt F. Ciliopathies. Cold Spring Harb Perspect Biol. 2017; 9(3).
Li J, Lu D, Liu H, Williams BO, Overbeek PA, Lee B, et al. Sclt1 deficiency causes cystic kidney by activating ERK and STAT3 signaling. Hum Mol Genet. 2017;26(15):2949–60.
Maddirevula S, Alzahrani F, Al-Owain M, Al Muhaizea MA, Kayyali HR, AlHashem A, et al. Autozygome and high throughput confirmation of disease genes candidacy. Genet Med. 2019;21(3):736–42.
Acknowledgements
The authors thank all the study participants and their families. We are profoundly grateful to Mrs. Yoshimi Nozu (Kobe University) for her excellent technical assistance. We would like to thank Editage (www.editage.jp) for English language editing. This work was supported by the Health Labor Sciences Research Grant for the Research on Measures for Intractable Diseases (H24-nanchi-ippan-041 to K.I.; H29-nanchi-ippan-039 to N.M.), and the Japan Society for the Promotion of Science (KAKENHI Grant number JP15K09261 and 18K08243 to N.M.).
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Kazumoto Iijima received funding support from Daiichi Sankyo Co., Ltd., Zenyaku Kogyo Co., Ltd. and Astellas Pharma, Inc.
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Morisada, N., Hamada, R., Miura, K. et al. Bardet–Biedl syndrome in two unrelated patients with identical compound heterozygous SCLT1 mutations. CEN Case Rep 9, 260–265 (2020). https://doi.org/10.1007/s13730-020-00472-y
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DOI: https://doi.org/10.1007/s13730-020-00472-y