Purpose

Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder.

Methods

We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed.

Results

We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing.

Conclusion

Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz–Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.

中文翻译：

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X连锁MED12中的从头功能丧失变异与女性哈迪卡综合征有关

目的

Hardikar 综合征 (MIM 612726) 是一种罕见的多发性先天性异常综合征，其特征是面部裂开、色素性视网膜病变、胆道异常和肠道旋转不良，但认知功能保留。之前只报告了四名患者，并且没有人进行分子诊断。我们的目标是确定 Hardikar 综合征 (HS) 的遗传基础并扩大这种疾病的表型谱。

方法

我们对两名先前报道和五名未发表的临床诊断为 HS 的女性患者进行了外显子组测序。还进行了 X 染色体失活 (XCI) 研究。

结果

我们报告了具有先前未描述表型的 HS 的临床特征，包括 21 岁时致命的无端颅内出血。我们还报告了在这 7 个个体中发现MED12从头致病性无意义和移码变异，以及在所有患有严重偏斜的 XCI 患者中的证据。信息测试。

结论

X 染色体基因MED12的致病性错义变异以前与 Opitz-Kaveggia 综合征、Lujan 综合征、Ohdo 综合征和非综合征性智力障碍有关，主要发生在男性中。我们提出了MED12的第五种女性特异性表型，并建议女性中的无意义和移码功能丧失MED12变体导致 HS。这将女性的MED12相关表型扩展到智力残疾之外。