Detection of novel gene variants associated with congenital hypothyroidism in a Finnish patient cohort
Löf, Christoffer; Patyra, Konrad; Kuulasmaa, Teemu; Vangipurapu, Jagadish; Undeutsch, Henriette; Jaeschke, Holger; Pajunen, Tuulia; Kero, Andreina; Krude, Heiko; Biebermann, Heike; Kleinau, Gunnar; Kühnen, Peter; Rantakari, Krista; Miettinen, Päivi; Kirjavainen, Turkka; Pursiheimo, Juha-Pekka; Mustila, Taina; Jääskeläinen, Jarmo; Ojaniemi, Marja; Toppari, Jorma; Ignatius, Jaakko; Laakso, Markku; Kero, Jukka (2016-09-01)
Detection of Novel Gene Variants Associated with Congenital Hypothyroidism in a Finnish Patient Cohort, Löf Christoffer, Patyra Konrad, Kuulasmaa Teemu, Vangipurapu Jagadish, Undeutsch Henriette, Jaeschke Holger, Pajunen Tuulia, Kero Andreina, Krude Heiko, Biebermann Heike, Kleinau Gunnar, Kühnen Peter, Rantakari Krista, Miettinen Päivi, Kirjavainen Turkka, Pursiheimo Juha-Pekka, Mustila Taina, Jääskeläinen Jarmo, Ojaniemi Marja, Toppari Jorma, Ignatius Jaakko, Laakso Markku, and Kero Jukka, Thyroid 2016, 26 9, 1215 -1224
©Christoffer Lo¨f et al. 2016; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncom- mercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Background: Congenital hypothyroidism (CH) is defined as the lack of thyroid hormones at birth. Mutations in at least 15 different genes have been associated with this disease. While up to 20% of CH cases are hereditary, the majority of cases are sporadic with unknown etiology. Apart from a monogenic pattern of inheritance, multigenic mechanisms have been suggested to play a role in CH. The genetics of CH has not been studied in Finland so far. Therefore, multigenic sequencing of CH candidate genes was performed in a Finnish patient cohort with both familial and sporadic CH.
Methods: A targeted next-generation sequencing (NGS) panel, covering all exons of the major CH genes, was applied for 15 patients with sporadic and 11 index cases with familial CH.
Results: Among the familial cases, six pathogenic mutations were found in the TPO, PAX8, and TSHR genes. Furthermore, pathogenic NKX2.1 and TG mutations were identified from sporadic cases, together with likely pathogenic variants in the TG, NKX2.5, SLC26A4, and DUOX2 genes. All identified novel pathogenic mutations were confirmed by Sanger-sequencing and characterized in silico and/or in vitro.
Conclusion: In summary, the CH panel provides an efficient, cost-effective, and multigenic screening tool for both known and novel CH gene mutations. Hence, it may be a useful method to identify accurately the genetic etiology for dyshormogenic, familial, or syndromic forms of CH.
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