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Biallelic loss‐of‐function HACD1 variants are a bona fide cause of congenital myopathy
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-12-22 , DOI: 10.1111/cge.13905 Lia Abbasi-Moheb 1 , Ana Westenberger 1, 2 , Maha Alotaibi 3 , Malak Ali Alghamdi 4 , Jozef L Hertecant 5 , Amir Ariamand 6 , Christian Beetz 1 , Arndt Rolfs 1, 7 , Aida M Bertoli-Avella 1, 7 , Peter Bauer 1
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-12-22 , DOI: 10.1111/cge.13905 Lia Abbasi-Moheb 1 , Ana Westenberger 1, 2 , Maha Alotaibi 3 , Malak Ali Alghamdi 4 , Jozef L Hertecant 5 , Amir Ariamand 6 , Christian Beetz 1 , Arndt Rolfs 1, 7 , Aida M Bertoli-Avella 1, 7 , Peter Bauer 1
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Congenital myopathies include a wide range of genetically determined disorders characterized by muscle weakness that usually manifest shortly after birth. To date, two different homozygous loss‐of‐function variants in the HACD1 gene have been reported to cause congenital myopathy. We identified three patients manifesting with neonatal‐onset generalized muscle weakness and motor delay that carried three novel homozygous likely pathogenic HACD1 variants. The two of these changes (c.373_375+2delGAGGT and c.785‐1G>T) were predicted to introduce splice site alterations, while one is a nonsense change (c.458G>A). The clinical presentation of our and the previously reported patients was comparable, including the temporally progressive improvement that seems to be characteristic of HACD1‐related myopathy. Our findings conclusively confirm the implication of HACD1 in the pathogenesis of congenital myopathies, corroborate the main phenotypic features, and further define the genotypic spectrum of this genetic form of myopathy. Importantly, the genetic diagnosis of HACD1‐related myopathy bears impactful prognostic value.
中文翻译：
双等位基因功能丧失 HACD1 变异是先天性肌病的真正原因
先天性肌病包括一系列以肌肉无力为特征的遗传性疾病，通常在出生后不久就出现。迄今为止，据报道， HACD1基因中有两种不同的纯合功能丧失变异体会导致先天性肌病。我们确定了三名表现出新生儿期全身性肌肉无力和运动迟缓的患者，这些患者携带三种新的纯合子可能致病的 HACD1变异。这些变化中的两个（c.373_375+2delGAGGT 和 c.785-1G>T）预计会引入剪接位点改变，而一个是无意义的变化（c.458G>A）。我们和之前报道的患者的临床表现具有可比性，包括似乎是HACD1相关的肌病。我们的研究结果最终证实了HACD1在先天性肌病发病机制中的意义，证实了主要的表型特征，并进一步确定了这种遗传形式的肌病的基因型谱。重要的是，HACD1相关肌病的基因诊断具有重要的预后价值。
更新日期：2020-12-22
中文翻译：
双等位基因功能丧失 HACD1 变异是先天性肌病的真正原因
先天性肌病包括一系列以肌肉无力为特征的遗传性疾病，通常在出生后不久就出现。迄今为止，据报道， HACD1基因中有两种不同的纯合功能丧失变异体会导致先天性肌病。我们确定了三名表现出新生儿期全身性肌肉无力和运动迟缓的患者，这些患者携带三种新的纯合子可能致病的 HACD1变异。这些变化中的两个（c.373_375+2delGAGGT 和 c.785-1G>T）预计会引入剪接位点改变，而一个是无意义的变化（c.458G>A）。我们和之前报道的患者的临床表现具有可比性，包括似乎是HACD1相关的肌病。我们的研究结果最终证实了HACD1在先天性肌病发病机制中的意义，证实了主要的表型特征，并进一步确定了这种遗传形式的肌病的基因型谱。重要的是，HACD1相关肌病的基因诊断具有重要的预后价值。
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