A case with somatic and germline mosaicism in COL4A5 detected by multiplex ligation-dependent probe amplification in X-l
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CASE REPORT
A case with somatic and germline mosaicism in COL4A5 detected by multiplex ligation‑dependent probe amplification in X‑linked Alport syndrome Yuya Aoto1 · Tomoo Kise2 · Koichi Nakanishi3 · China Nagano1 · Tomoko Horinouchi1 · Tomohiko Yamamura1 · Shinya Ishiko1 · Nana Sakakibara1 · Yuko Shima4 · Naoya Morisada1 · Kazumoto Iijima1 · Kandai Nozu1 Received: 10 April 2020 / Accepted: 28 June 2020 © Japanese Society of Nephrology 2020
Abstract X-linked Alport syndrome (XLAS) is a progressive hereditary kidney disease caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain. To date, 11 cases having somatic mosaic variants in COL4A5 have been reported; however, all of them involved single-nucleotide variations (SNVs). Here, we report a female XLAS patient with somatic mosaicism identified by copy number variation (CNV) in COL4A5. The case was a 35-year-old female, the mother of the proband, whose only clinical symptom was hematuria. The proband, who was the son of this patient, was diagnosed with XLAS by gene testing, which showed a large hemizygous deletion from exon 3–51 in COL4A5 detected by next-generation sequencing and then confirmed by multiplex ligation-dependent probe amplification (MLPA). Then, MLPA analysis revealed that the female patient had the same deletion with only a 20% copy number reduction compared with a normal female control; she was thus diagnosed with XLAS with somatic mosaicism. CNVs in COL4A5 are relatively rare and, to the best of our knowledge, somatic mosaic variants with CNVs have never been reported. This case clearly featured a germline variant because the patient’s son exhibited XLAS. This is thus the first case report on an XLAS patient having CNV in COL4A5 with somatic mosaicism. The obtained findings were very important for the genetic counseling of this family. Keywords X-linked alport syndrome · Type IV collagen α5 · Mosaicism · Copy number variation · Multiplex ligationdependent probe amplification · Next-generation sequencing
Introduction
* Yuya Aoto [email protected]‑u.ac.jp 1
Department of Pediatrics, Kobe University Graduate School of Medicine, 7‑5‑1 Kusunoki‑cho, Chuo‑ku, Kobe 650‑0017, Japan
2
Division of Pediatric Nephrology, Okinawa Prefectural Nanbu Medical Center, Children’s Medical Center, 118‑1 Arakawa, Haebaru‑cho, Simajiri‑gun, Okinawa 901‑1105, Japan
3
Department of Pediatrics, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara‑cho, Nakagami‑gun, Okinawa 903‑0125, Japan
4
Department of Pediatrics, Wakayama Medical University, 811‑1 Kimiidera, Wakayama 641‑8509, Japan
Alport syndrome is a progressive hereditary renal disease, which develops into end-stage renal disease (ESRD), sensorineural hearing loss, and ocular abnormalities. Approximately 80% of Alport syndrome patients have an X-linked (XLAS) condition, caused by pathogenic variants in the COL4A5 gene encoding type IV collagen α5 chain [α5 (IV)]. Typically, male XLAS patients progress to ESRD in their 20–30 s [1–4], while female
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