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. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX 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 SHOX: 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 SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual.

中文翻译：

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Leri-Weill 软骨骨发育不良由漏纯合子 SHOX 剪接位点变异引起

SHOX 缺陷是不同程度矮小的常见遗传原因。SHOX 单倍体不足会导致 Leri–Weill 软骨发育不良 (LWD) 以及非特异性矮小症。已知 SHOX 单倍体不足是由具有假常染色体显性遗传的杂合功能丧失变异引起的，而双等位基因 SHOX 功能丧失变异导致更严重的骨骼发育不良，Langer 中部软骨发育不良 (LMD)。在这里，我们首次报告了两个兄弟姐妹中 LWD 的假常染色体隐性遗传，该遗传是由 SHOX 的内含子 3 中的一种新型纯合非规范漏剪接位点变异引起的：c.544+5G>C。患者来源的成纤维细胞的转录本分析显示，纯合子患者产生大约等量的正常剪接 mRNA 和异常保留内含子 3 并含有过早终止密码子的 mRNA (p.Val183Glyfs*31)。异常的转录物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 单倍体不足。六名身高正常的健康亲属是该变异体的杂合子，来自 c.544+5G>C 变异体杂合子的成纤维细胞产生的野生型转录物数量与健康对照相当。这里报告的独特情况强调了一个事实，即 SHOX 的剂量决定了临床表型，而不是 SHOX 变体的孟德尔遗传模式。