Newborn screening and single nucleotide variation profiling of TSHR , TPO , TG and DUOX2 candidate genes for congenital
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ORIGINAL ARTICLE
Newborn screening and single nucleotide variation profiling of TSHR, TPO, TG and DUOX2 candidate genes for congenital hypothyroidism Yedukondalu Kollati1 · Radha Rama Devi Akella2,3 · Shaik Mohammad Naushad3 · Divya Borkar3 · Maunika Thalla3 · Swapna Nagalingam4 · Lokesh Lingappa5 · Rajesh K. Patel6 · G. Bhanuprakash Reddy4 · Vijaya R. Dirisala1 Received: 20 June 2020 / Accepted: 3 September 2020 © Springer Nature B.V. 2020
Abstract High prevalence of congenital hypothyroidism (CH) among Indian newborns prompted us to establish population-specific reference ranges of TSH and to explore the contribution of the common genetic variants in TSHR, TPO, TG and DUOX2 genes towards CH. A total of 1144 newborns (593 males and 551 females) were screened for CH. SNV profiling (n = 22) spanning three candidate genes, i.e. TSHR, TPO and TG was carried out in confirmed CH cases (n = 45). In screen negative cases (n = 700), ten TSHR variants were explored to establish association with CH. No mutation found in DUOX2. The 2.5th to 97.5th percentiles of TSH in these newborns were 0.5 to 12.2 mU/L. In newborns with optimal birth weight, the cut-off was 10 mU/L. Lower or higher birth weight resulted in slightly higher TSH. Two TSHR variants, i.e. rs7144481 and rs17630128 were associated with agenesis, hypoplasia and goiter. The rs2268477 was associated with agenesis and hypoplasia. The rs1991517, rs2075176 and rs2241119 were associated with agenesis only. The rs7144481, rs17630128, rs1991517 and rs2268477 were associated with 2.17, 4.62, 2.91 and 2.29-fold increased risk for CH, respectively. Among the TPO variants, rs867983 and rs2175977 were associated with agenesis and goiter, respectively. Among the TG variants, rs2076740 showed association with agenesis and goiter. Two rare variants i.e. TPO g.IVS14-19 G>C and TG c.1262 C>T were observed in CH cases. No genetic variant identified in the two exons of DUOX2. To conclude, the current study established Indian population-specific normative values for TSH and demonstrates specific genotype–phenotype correlations among three candidate genes. Keywords Congenital hypothyroidism · TSHR · TPO · TG · DUOX2 · Newborn screening
Introduction Yedukondalu Kollati and Radha Rama Devi Akella contributed equally to this study. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11033-020-05803-x) contains supplementary material, which is available to authorized users. * G. Bhanuprakash Reddy [email protected] * Vijaya R. Dirisala [email protected] 1
2
Department of Biotechnology, Vignan’s Foundation for Science, Technology & Research (Deemed to be University), Vadlamudi, Guntur, Andhra Pradesh 522213, India Department of Genetics, Rainbow Children’s Hospital, Banjara Hills, Hyderabad, Telangana 500009, India
Congenital hypothyroidism (CH) is one of the most prevalent metabolic disorders in the newborn with a prevalence of 1:4000 globally [1, 2] and 1:1100 in India [3]. CH is classified into permanent CH and transient
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