两个截短型MITF变异扩展了COMMAD综合征的表型谱

文献信息

中文摘要

背景： MITF（小眼畸形相关转录因子）基因的致病性变异与一系列疾病相关，包括Waardenburg综合征II型和Tietz综合征。罕见报道提示，双等位基因功能丧失变异可能导致严重的多系统表型。我们报告了一名婴儿，其表型符合COMMAD样综合征（缺损、骨硬化、小眼畸形、大头畸形、白化病和耳聋），并在新生儿早期死亡。除了核心COMMAD特征外，先证者还表现出异位骨化、心脏纤维化和纤维弹性组织增生、间质性肺病、异位肾组织、肝脂肪变性和含铁血黄素沉着症。全外显子组测序鉴定出两个杂合截短型MITF变异：先前报道的c.961C>T（p.Arg321Ter）和一个新的c.1135A>T（p.Lys379Ter）变异，两者均预测会导致MITF功能受损。父母检测被拒绝，无法确定变异的相位。迄今为止，仅有一项研究报告了双等位基因MITF破坏与严重临床表型之间的关联。我们的发现为这种基因型-表型关系提供了额外证据，并进一步扩展了COMMAD综合征的临床谱。本病例进一步支持MITF功能受损在严重多系统表型发病机制中的作用。

英文摘要

Pathogenic variants in MITF (Microphthalmia Transcription Factor) gene are associated with a spectrum of disorders, including Waardenburg syndrome type II and Tietz syndrome. Rare reports suggest that biallelic loss-of-function variants may result in a severe multisystem phenotype. We report an infant presenting with a phenotype consistent with COMMAD-like syndrome (Coloboma, Οsteopetrosis, Μicrophthalmia, Μacrocephaly, Αlbinism, and Deafness) who died in the early neonatal period. In addition to the core COMMAD features, the proband exhibited ectopic ossification, cardiac fibrosis and fibroelastosis, interstitial lung disease, ectopic renal tissue, liver steatosis, and hemosiderosis. Whole-exome sequencing identified two heterozygous truncating MITF variants, the previously reported c.961C>T (p.Arg321Ter) and a novel c.1135A>T (p.Lys379Ter) variant, both predicted to result in impaired MITF function. Parental testing was declined, precluding determination of the phase of the variants. To date, only one study has reported an association between biallelic MITF disruption and a severe clinical phenotype. Our findings provide additional evidence for this genotype-phenotype relationship and further expand the clinical spectrum of COMMAD syndrome. The present case further supports a role for impaired MITF function in the pathogenesis of a severe multisystem phenotype.