진단되지 않은 증후군성 저신장 또는 과성장 소아에서 차세대 시퀀싱의 임상적 유용성
Clinical utility of next generation sequencing for undiagnosed pediatric patients with syndromic short stature or overgrowth
Abstract
Purpose: Next generation sequencing (NGS) is effective for multiple gene screening. This study was for detecting causative gene in Korean pediatric patients with short stature or overgrowth using exome sequencing. Methods: This study included 10 patients with short stature and one overgrowth patient from 10 unrelated families. In short stature group, the mean height SDS of patients was –2.92 SDS. Three patients were born with small for gestational age. Nine patients showed dysmorphic face or developmental delay and three patients had family history of short stature and brittle teeth. An overgrowth patient was tall (2.13 SDS) and floppy. Five patients had congenital heart disease. All of them were failed to detect genetic cause using single gene sequencing or karyotyping. Diagnostic exome sequencing (DES, Greencross medical genetics) was performed using Nextseq (illumina) and TruSight one sequencing panel capturing 4,813 genes and 62,000 exons. Clinical features, growth, laboratory and radiologic finding, and neurodevelopmental state were reviewed, respectively. Results: We identified a genetic cause of short stature in four of the 10 patients and one overgrowth patient suspected Loeys-Dietz syndrome. A overgrowth patient had a missense mutation p.Arg300Gln of i>TGFB3/i>. Two patients suspected with Noonan syndrome were diagnosed with Coffin-Lowry syndrome and trichorhinophalangeal (TRP) syndrome, respectively. A Coffin-Lowry syndrome patient also had congenital glaucoma and the genetic testing revealed not only p.Arg112* of i>RPS6KA3/i> but also compound heterozygote mutations of i>CYP1B1/i> for congenital glaucoma. A TRP syndrome patient had a novel mutation p.Lys779Glufs*26 of i>TRPS1/i>. Two sibling showing severe short stature, protosis, brachydactyly, and recurrent hepatic failure were diagnosed with short stature with optic atrophy and Pelger Huet anomaly (SOPH) syndrome confirmed by compound heterozygote mutations for novel splicing and p.Arg1914His of i>NBAS/i>. Conclusions: We identified four different diseases from five patients of 10 families (40%) using DES. Four of them were diagnosed with unexpected disease. NGS is useful for syndromic disorder having several candidate genes. Our data could contribute to a better understanding for the genetic causes in growth disorder and the application of DES in pediatric patients.