简介遗传分析在评估身材矮小儿童中的诊断率取决于相关的临床特征,但是父母血亲的额外影响还没有得到很好的记录。方法由六个儿科内分泌学转诊中心收集来自34个近亲家庭的42名矮小儿童的观察性病例系列(纳入标准:身材矮小和父母近亲)。在18名患者(12个家庭,Group1),临床特征提示生长激素(GH)-胰岛素样生长因子I(IGF-I)轴中存在特定的遗传缺陷,并使用了候选基因方法。在其他(第2组)中,选择了无假设的方法(基因面板,微阵列分析,和全外显子组测序),进一步细分为11例严重身材矮小(身高<-3.5SDS)和小头畸形(头围<-3.0SDS)(2a组),10例综合征性身材矮小(2b组)和3例非特异性孤立性GH缺乏症(2c组)。结果在第1组的所有12个家庭中,(可能)在GHR中鉴定出致病性变异,IGFALS,GH1和STAT5B。在2a组的9/12家庭中,在PCNT中检测到变异,SMARCAL1,SRCAP,WDR4和GHSR。在2b组的5/9家庭中,在TTC37,SCUBE3,NSD2,RABGAP1和17p13.3微缺失中发现了变异.2c组未发现遗传原因。纯合子,在21、1和4例患者中发现了复合杂合和杂合变体,分别。结论对父母近亲的矮小儿童进行基因检测具有较高的诊断率,特别是在严重的GH缺乏或不敏感的情况下,小头畸形,和综合征性身材矮小。
BACKGROUND: The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental
consanguinity has not been well documented.
METHODS: This observational case series of 42 short children from 34 consanguineous families was collected by six referral centres of paediatric endocrinology (inclusion criteria: short stature and parental
consanguinity). In 18 patients (12 families, group 1), the clinical features suggested a specific genetic defect in the growth hormone (GH) insulin-like growth factor I (IGF-I) axis, and a candidate gene approach was used. In others (group 2), a hypothesis-free approach was chosen (gene panels, microarray analysis, and whole exome sequencing) and further subdivided into 11 patients with severe short stature (height <-3.5 standard deviation score [SDS]) and microcephaly (head circumference <-3.0 SDS) (group 2a), 10 patients with syndromic short stature (group 2b), and 3 patients with nonspecific isolated GH deficiency (group 2c).
RESULTS: In all 12 families from group 1, (likely) pathogenic variants were identified in GHR, IGFALS, GH1, and STAT5B. In 9/12 families from group 2a, variants were detected in PCNT, SMARCAL1, SRCAP, WDR4, and GHSR. In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions. In group 2c, no genetic cause was found. Homozygous, compound heterozygous, and heterozygous variants were found in 21, 1, and 4 patients, respectively.
CONCLUSIONS: Genetic testing in short children from consanguineous parents has a high diagnostic yield, especially in cases of severe GH deficiency or insensitivity, microcephaly, and syndromic short stature.