Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Clin Endocrinol Metab. 2013 Aug;98(8):E1428-37. doi: 10.1210/jc.2013-1534. Epub 2013 Jun 14.
The majority of patients presenting with short stature do not receive a definitive diagnosis. Advances in genetic sequencing allow for large-scale screening of candidate genes, potentially leading to genetic diagnoses.
The purpose of this study was to discover genetic variants that contribute to short stature in a cohort of children with no known genetic etiology.
This was a prospective cohort study of subjects with short stature.
The setting was a pediatric endocrinology and genetics clinics at an academic center.
A total of 192 children with short stature with no defined genetic etiology and 192 individuals of normal stature from the Framingham Heart Study were studied.
Pooled targeted sequencing using next-generation DNA sequencing technology of the exons of 1077 candidate genes was performed.
The numbers of rare nonsynonymous genetic variants found in case patients but not in control subjects, known pathogenic variants in case patients, and potentially pathogenic variants in IGF1R were determined.
We identified 4928 genetic variants in 1077 genes that were present in case patients but not in control subjects. Of those, 1349 variants were novel (898 nonsynonymous). False-positive rates from pooled sequencing were 4% to 5%, and the false-negative rate was 0.1% in regions covered well by sequencing. We identified 3 individuals with known pathogenic variants in PTPN11 causing undiagnosed Noonan syndrome. There were 9 rare potentially nonsynonymous variants in IGF1R, one of which is a novel, probably pathogenic, frameshift mutation. A previously reported pathogenic variant in IGF1R was present in a control subject.
Large-scale sequencing efforts have the potential to rapidly identify genetic etiologies of short stature, but data interpretation is complex. Noonan syndrome may be an underdiagnosed cause of short stature.
大多数身材矮小的患者未得到明确诊断。基因测序技术的进步使得对候选基因进行大规模筛查成为可能，从而可能导致遗传诊断。
本研究旨在发现导致无已知遗传病因的矮小儿童身材矮小的遗传变异。
这是一项对身材矮小患者进行的前瞻性队列研究。
学术中心的儿科内分泌学和遗传学诊所。
研究了 192 名身材矮小且无明确遗传病因的儿童和 192 名来自弗雷明汉心脏研究的正常身高个体。
对 1077 个候选基因的外显子进行了下一代 DNA 测序技术的靶向测序。
确定在病例患者中发现但在对照患者中未发现的罕见非同义遗传变异的数量、病例患者中的已知致病性变异以及 IGF1R 中的潜在致病性变异。
我们在 1077 个基因中发现了存在于病例患者但不存在于对照患者中的 4928 个遗传变异。其中，1349 个变异是新的（898 个非同义）。来自混合测序的假阳性率为 4%至 5%，在测序覆盖良好的区域，假阴性率为 0.1%。我们发现 3 名患有导致未确诊的努南综合征的 PTPN11 已知致病性变异的患者。IGF1R 中有 9 个罕见的潜在非同义变异，其中一个是新的、可能是致病性的、移码突变。IGF1R 中之前报道的致病性变异存在于对照患者中。
大规模测序工作有可能快速确定身材矮小的遗传病因，但数据解释较为复杂。努南综合征可能是身材矮小的一个未被充分诊断的原因。
