Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
Vienna Bone and Growth Center, 1130 Vienna, Austria.
Genes (Basel). 2023 Apr 7;14(4):877. doi: 10.3390/genes14040877.
SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri-Weill dyschondrosteosis (LWD) as well as nonspecific short stature. haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of c.544+5G>C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G>C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual.
SHOX 缺陷是一种常见的遗传原因导致不同程度的身材矮小。SHOX 杂合性不足会导致 Leri-Weill 软骨发育不全症（LWD）以及非特异性身材矮小。杂合性不足已知是由于具有拟常染色体显性遗传的杂合性功能丧失变异引起的，而等位基因缺失性功能丧失变异会导致更严重的骨骼发育不良，Langer 中胚层软骨发育不全症（LMD）。在这里，我们首次报道了两个同胞中 LWD 的拟常染色体隐性遗传，这是由 c.544+5G>C 中内含子 3 的新型纯合非典型、渗漏剪接位点变异引起的。在患者来源的成纤维细胞中的转录分析表明，纯合子患者产生等量的正常剪接 mRNA 和含有异常保留内含子 3 并含有提前终止密码子（p.Val183Glyfs*31）的 mRNA。异常转录本被证明会经历无意义介导的 mRNA 衰变，从而导致纯合子患者的 SHOX 杂合性不足。六个身高正常的健康亲属为该变异的杂合子，而 c.544+5G>C 变异的杂合子的成纤维细胞产生的野生型转录本数量与健康对照相当。这里报道的独特情况突出了这样一个事实，即 SHOX 的剂量决定了临床表型，而不是 变异的孟德尔遗传模式。本研究扩展了 SHOX 缺陷疾病的分子和遗传谱，并强调了对未知意义的 变异进行功能测试的重要性，以便为每个家庭个体提供适当的咨询和精准医疗。
