ESPE Abstracts (2018) 89 P-P2-264

Targeted/Exome Sequencing Identified Mutations in 55 Chinese Children Diagnosed with Noonan Syndrome and a Autosomal Recessive form Associated with LZTR1 Variants

Xin Lia, Ruen Yaoa, Yao Chena, Guoying Changa, Yu Dinga, Juan Lia, Yiping Shenb, Xiumin Wanga & Jian Wanga

aShanghai Children’s Medical Center, Shanghai, China; bBoston Children’s Hospital, Boston, MA, USA

Background: Noonan syndrome (NS) is generally considered an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. The latest research confirmed the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1. In this study, we diagnosed 55 Chinese NS Children via targeted sequencing or whole exome sequencing (TS/WES).

Methods: TS/WES was performed to identify mutations in 55 Chinese Children who exhibited the following manifestations: potential NS facial dysmorphisms, short stature, congenital heart defects, and developmental delay. Sanger sequencing was used to confirm the suspected pathological variants in the patients and their family members.

Results: TS/WES revealed 25 NS patients (45.5%) caused by mutation in PTPN11 gene, 10 NS patients(18.2%)caused by mutation in SOS1 gene, 6 NS patients(10.9%)caused by mutation in SHOC2, 6 NS patients (10.9%) caused by mutation in KRAS gene, 3 mutations in the MAP2K1 gene, 2 mutations in RAF1 gene and 2 mutations in RIT1 gene. Specially, we identified a NS patient with a novel compound heterozygous mutation in the LZTR1 gene and inherited in an autosomal recessive pattern.

Conclusions: TS/WES has emerged as a useful tool for definitive diagnosis and accurate genetic counseling of atypical cases. This is a large sample study using TS/WES to diagnose Chinese patients with Noonan syndrome, and helping to reveal gene spectrum of Chinese NS patients. Our study also identified an autosomal recessive pattern in NS Patients with novel mutations in LZTR1. And it is the first report about a Chineses NS Patient with mutations in LZTR1 and Changed our traditional understanding about the inherited pattern of Noonan syndrome.