Identifying TPO And TSHR Mutations From Chinese Congenital Hypothyroidism Patients

Several genes are reported to be associated with congenital hypothyroidism(CH).This study aimed to identify TPO and TSHR mutations in Chinese patients with CH and analyze the phenotypes of TPO and TSHR mutation carries.We screened for TPO and TSHR mutations in 184 patients with primary CH by performing next-generation sequencing.The function of 3 novel and 5 biallelic mutation sites in TSHR were further examined.Among 184 patients with CH,13 distinct TPO mutations were identified in 17 patients(9.23%,17/184),2 were hotspot mutations(C756fs and A443 P were carried by 7 and 3 patients,respectively),3 were novel mutations(C269S,A430 E and E799D),4 patients carried with biallelic mutations and two pedigrees indicated TPO mutations inherited in an autosomal recessive fashion.13 distinct TSHR mutations were identified in 11 patients(5.98%,11/184),3 were novel mutations and one was a hotspot mutation(R450H,were carried by 2 patients).Moreover,3 patients carried with biallelic mutations of TSHR.We found that 5 biallelic mutations(G132R,I216 T,A275T,R450 H,and R528S)and 2(N372T,S567R)out of 3 novel mutations were loss-of-function mutations.In patients with CH,the thyroid stimulating hormone level was lower in who harbored TSHR mutations than that in those without TSHR mutations.Of 184 patients with CH,2 of the loss-of-function biallelic TSHR mutation carriers required higher dose of thyroid hormone(100 and 150 ug/day)to maintain normal thyroid function compared to the mean maintenance dose of levothyroxine(44.5 ug/day).Our study indicated that TPO and TSHR mutations are common in Chinese patients with CH.We found that patients with CH who harbor TSHR mutations exhibit distinct phenotypes compared to those without TSHR mutations.3 novel TSHR mutations were found and 2 of them could impair function.