身材矮小
特发性矮身高
移码突变
骨生长
阿格里坎
内分泌学
错义突变
骨龄
内科学
遗传学
医学
外显子
外显子组测序
软骨发育不全
突变
生物
病理
基因
骨关节炎
生长激素
关节软骨
替代医学
激素
作者
Ola Nilsson,Michael H. Guo,Nancy Dunbar,Jadranka Popović,Daniel Flynn,Christina M. Jacobsen,Julian C. Lui,Joel N. Hirschhorn,Jeffrey Baron,Andrew Dauber
摘要
Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common.The aim was to identify underlying genetic causes of short stature with advanced bone age.We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation.Affected individuals presented with short stature [adult heights -2.3 to -4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS -1.9 to -3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c.2026+1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function.Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation.
科研通智能强力驱动
Strongly Powered by AbleSci AI