A novel pathogenic mutation in FBN2 associated with congenital contractural arachnodactyly for preimplantation genetic diagnosis

Jiaxin Li^{1, 1},
Yuqian Wang^{2, 3, 1},
Xiaohui Zhu^{2, 3},
Yanli Nie^{2, 3},
Ying Kuo^{2, 3},
Shuo Guan^{2, 3},
Jin Huang^{2, 3},
Ying Lian^{2, 3},
Yangyu Zhao^{2, 3},
Rong Li^{2, 3},
Yuan Wei⁴,
Jie Qiao^{5, 6, 7, 8},
Liying Yan^{9, 10
, ,}

1.
Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
2.
Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
3.
Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China
4.
Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
5.
Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
6.
Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China
7.
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100191, China
8.
Beijing Advanced Innovation Center for Genomics, Peking University, Beijing 100191, China
9.
Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
10.
Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China

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Corresponding author: E-mail address: yanliyingkind@aliyun.com (Liying Yan)

Jiaxin Li and Yuqian Wang contributed equally to this work.

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Jiaxin Li and Yuqian Wang contributed equally to this work.

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Fig. 1. Verification of the pathogenic mutation (FBN2, c.3719G > A) of this CCA family.A: Pedigree of this CCA family. Filled symbols marked with red numbers represent individuals affected by CCA; open symbols marked with black numbers represent wild-type individuals. Circles and squares indicate females and males, respectively. The couple indicated by red asterisks asked for PGD treatment. B: Sanger sequencing detection of FBN1 mutation (c.698G > A) for the entire family. Red G/A and arrow marked individuals carry this heterozygous mutation. Orange boxes highlight that phenotypes and genotypes are at odds.C: Pathogenicity prediction of FBN2, c.3719G > A by MutationTaster-2. This variant was not found in ExAC or 1000G, and it is highly possible that the mutation causes disease.D: Pathogenicity prediction of FBN2, c.3719G > A by PolyPhen-2. This mutation was predicted to be damaging with a score of 0.996 (score ranges from 0 to 1, and the higher the score, the higher the pathogenicity).E: Sanger sequencing detection of FBN2 mutation (c.3719G > A) for the entire family. Individuals marked with a red G/A and arrow carry this heterozygous mutation, and the mutation corresponds to the incidence in these families.F: Conservation analysis of 1240C and protein structure change after C1240Y. Modeled structures of cbEGF Domains 18 and 19 of the FBN2 protein were illustrated in the wild type and mutation. The wild-type and mutant sequences of cbEGF Domains 18 and 19 are provided in Supplementary data (supplementary file 1 and 2). cbEGF, calcium-binding epidermal growth factor–like; CCA, congenital contractural arachnodactyly; PGD, preimplantation genetic diagnosis.

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