Ayla Guven1,2, Roua A Al-Rijjal3, Huda A BinEssa3, Durmuş Dogan4, Yılmaz Kor5, Minjing Zou2, Namik Kaya3, Anwar F Alenezi3, Suna Hancili1,2, Ömer Tarım4, Essa Y Baitei3, Walaa E Kattan3, Brian F Meyer3, Yufei Shi3. 1. Department of Pediatric, Amasya University Medical Faculty, Amasya, Turkey. 2. Pediatric Endocrinology Clinic, Goztepe Educational and Research Hospital, Istanbul, Turkey. 3. Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. 4. Department of Pediatrics, Division of Pediatric Endocrinology, Uludag University Faculty of Medicine, Bursa, Turkey. 5. Pediatric Endocrinology Division, Adana Numune Training and Research Hospital, Adana, Turkey.
Abstract
CONTEXT: Hypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3. OBJECTIVE: To investigate underlying genetic defects in patients with hypophosphataemic rickets. METHODS: We analysed genomic DNA from nine unrelated families for mutations in the entire coding region of PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3 by PCR sequencing and copy number analysis. RESULTS: A total of 14 patients were studied. PHEX mutations were identified in 12 patients from seven families. Five of them were novel mutations present in eight patients: c.154G>T (p.E52*), c.401_402insGCCAAA (p.Q134_K135insPK), c.1600C>T (p.P534S), g.22016715_22056805del (40-kb deletion including promoter and exons 1-3) and c.2242_2243delCT (p.L748 fs*48). Four patients had previously reported mutations: c.1768+1G>A and c.1807G>A (p.W602*). Novel CLCN5 (c.1205G>A, p.W402*) and FGF23 (c.526C>G, p.R176G) mutations were found in two patients from the remaining two families. Many of the mutations were de novo: c.154G>T and c.2242_2243delCT in PHEX and c.526C>G in FGF23. Furthermore, we characterized the breakpoint of the novel PHEX g.22016715_22056805del and the c.2242_2243delCT, which is 6 bp from the stop codon, resulting in a frameshift and extension of the reading frame by 42 amino acids. CONCLUSIONS: Novel and de novo mutations are frequent and PHEX mutations are still the most common genetic defects in the Turkish population. Gene copy number analysis should be considered in patients with negative results by conventional PCR-based sequencing analysis. The current study further expands the mutation spectrum underlying HR.
CONTEXT: Hypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3. OBJECTIVE: To investigate underlying genetic defects in patients with hypophosphataemic rickets. METHODS: We analysed genomic DNA from nine unrelated families for mutations in the entire coding region of PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3 by PCR sequencing and copy number analysis. RESULTS: A total of 14 patients were studied. PHEX mutations were identified in 12 patients from seven families. Five of them were novel mutations present in eight patients: c.154G>T (p.E52*), c.401_402insGCCAAA (p.Q134_K135insPK), c.1600C>T (p.P534S), g.22016715_22056805del (40-kb deletion including promoter and exons 1-3) and c.2242_2243delCT (p.L748 fs*48). Four patients had previously reported mutations: c.1768+1G>A and c.1807G>A (p.W602*). Novel CLCN5 (c.1205G>A, p.W402*) and FGF23 (c.526C>G, p.R176G) mutations were found in two patients from the remaining two families. Many of the mutations were de novo: c.154G>T and c.2242_2243delCT in PHEX and c.526C>G in FGF23. Furthermore, we characterized the breakpoint of the novel PHEXg.22016715_22056805del and the c.2242_2243delCT, which is 6 bp from the stop codon, resulting in a frameshift and extension of the reading frame by 42 amino acids. CONCLUSIONS: Novel and de novo mutations are frequent and PHEX mutations are still the most common genetic defects in the Turkish population. Gene copy number analysis should be considered in patients with negative results by conventional PCR-based sequencing analysis. The current study further expands the mutation spectrum underlying HR.
Authors: Eric T Rush; Britt Johnson; Swaroop Aradhya; Daniel Beltran; Sara L Bristow; Scott Eisenbeis; Norma E Guerra; Stan Krolczyk; Nicole Miller; Ana Morales; Prameela Ramesan; Soodabeh Sarafrazi; Rebecca Truty; Kathryn Dahir Journal: J Bone Miner Res Date: 2021-11-10 Impact factor: 6.390
Authors: Sezer Acar; Huda A BinEssa; Korcan Demir; Roua A Al-Rijjal; Minjing Zou; Gönül Çatli; Ahmet Anık; Anwar F Al-Enezi; Seçil Özışık; Manar S A Al-Faham; Ayhan Abacı; Bumin Dündar; Walaa E Kattan; Maysoon Alsagob; Salih Kavukçu; Hamdi E Tamimi; Brian F Meyer; Ece Böber; Yufei Shi Journal: PLoS One Date: 2018-03-05 Impact factor: 3.240