Biallelic deletion in a minimal CAPN15 intron in siblings with a recognizable syndrome of congenital malformations and developmental delay,Clinical Genetics

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Biallelic deletion in a minimal CAPN15 intron in siblings with a recognizable syndrome of congenital malformations and developmental delay
Clinical Genetics ( IF 2.9 ) Pub Date : 2021-01-07 , DOI: 10.1111/cge.13920
Hagar Mor-Shaked _{1,

2} , Somaya Salah _{1,

3} , Shira Yanovsky-Dagan ₁ , Vardiella Meiner _{1,

2} , Osama M Atawneh ₄ , Bassam Abu-Libdeh ₅ , Orly Elpeleg _{1,

2} , Tamar Harel _{1,

2}

Affiliation

Calpainopathies constitute a heterogeneous group of disorders resulting from deficiencies in calpains, calcium‐specific proteases that modulate substrates by limited proteolysis. Clinical manifestations depend on tissue‐specific expression of the defective calpain and substrate specificity. CAPN15, encoding the Drosophila small optic lobes (sol) homolog, was recently found to cause various eye defects in individuals carrying bi‐allelic missense variants. Here we report on two siblings with manifestations reminiscent of Johanson‐Blizzard syndrome including failure to thrive, microcephaly, global developmental delay, dysmorphic features, endocrine abnormalities and congenital malformations, in addition to eye abnormalities. Exome sequencing identified a homozygous 47 base‐pair deletion in a minimal intron of CAPN15, including the splice donor site. Sequencing of cDNA revealed single exon skipping, resulting in an out‐of‐frame deletion with a predicted premature termination codon. These findings expand the phenotypic spectrum associated with CAPN15 variants, and suggest that complete loss‐of‐function is associated with a recognizable syndrome of congenital malformations and developmental delay, overlapping Johanson‐Blizzard syndrome and the recently observed brain defects in Capn15 knockout (KO) mice. Moreover, the data highlight the unique opportunity for indel detection in minimal introns.

中文翻译：

具有可识别的先天畸形和发育迟缓综合征的兄弟姐妹中最小 CAPN15 内含子的双等位基因缺失

钙蛋白酶病是由钙蛋白酶缺乏引起的一组异质性疾病，钙蛋白酶是通过有限的蛋白水解调节底物的钙特异性蛋白酶。临床表现取决于有缺陷的钙蛋白酶的组织特异性表达和底物特异性。CAPN15编码果蝇小视叶 (sol) 同源物，最近被发现会导致携带双等位基因错义变体的个体出现各种眼睛缺陷。在这里，我们报告了两个兄弟姐妹的表现让人想起 Johanson-Blizzard 综合征，包括发育迟缓、小头畸形、整体发育迟缓、畸形特征、内分泌异常和先天性畸形，以及眼睛异常。外显子组测序鉴定出一个 47 个碱基对的纯合子缺失内含子的最小内含子。CAPN15，包括剪接供体位点。cDNA 测序显示单个外显子跳跃，导致框外缺失和预测的提前终止密码子。这些发现扩展了与CAPN15变体相关的表型谱，并表明完全丧失功能与可识别的先天畸形和发育迟缓综合征、Johanson-Blizzard 综合征和最近观察到的Capn15敲除 (KO)脑缺陷有关老鼠。此外，数据突出了在最小内含子中检测插入缺失的独特机会。

更新日期：2021-03-05

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