Ataxia-telangiectasia is a rare autosomal recessive, neurodegenerative disorder caused by alterations in the ATM gene. The majority of ATM pathogenic variants are frameshift or nonsense variants which are predicted to truncate the whole ATM protein. Herein, we report on an ataxia telangiectasia child with atypical phenotype who was identified as compound heterozygous for two ATM variants involving a previously described pathogenic single nucleotide variation (SNV) and a novel copy number variation (CNV). A 6-year-old boy presented with delayed development and oculomotor apraxia. Brain magnetic resonance imaging showed interval development of mild atrophy in the cerebellum. Serum alpha fetoprotein level was in normal range. Next-generation sequencing and single-nucleotide polymorphism array tests were performed. Next-generation sequencing revealed a heterozygous nonsense pathogenic variant in ATM, c.742C > T (p.Arg248Ter) inherited from the father. Single-nucleotide polymorphism array revealed a compound heterozygous CNV, arr[GRCh37] 11q22.3(10851766–108183226) × 1, 31460 bp (exons 24–40 deletion of ATM) inherited from the mother, which was validated by reverse transcription-polymerase chain reaction analysis (RT-PCR). We demonstrated that this variant (NM_000051.4:c.3403_6006del) generated a product of in-frame deletion of exon 24–40 of ATM (p.Ser1135_Gln2002del). The compound heterozygosity for ATM variants involving a previously described pathogenic SNV and a novel CNV may be associated with the atypical clinical manifestations. This clinical report extends the genetic and phenotypic spectrum of ATM pathogenic variants in atypical ataxia-telangiectasia, thus making implementation of advanced analysis beyond the routine next-generation sequencing an important consideration in diagnosis and rehabilitation services for children with ataxia-telangiectasia.

中文翻译：

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复合杂合变异，包括非典型共济失调毛细血管扩张症儿童的新拷贝数变异：病例报告


共济失调毛细血管扩张症是一种罕见的常染色体隐性遗传神经退行性疾病，由 ATM 基因改变引起。大多数 ATM 致病变异是移码或无义变异，预计会截断整个 ATM 蛋白。在此，我们报告了一名具有非典型表型的共济失调性毛细血管扩张儿童，该儿童被鉴定为两种 ATM 变异的复合杂合子，涉及先前描述的致病性单核苷酸变异 (SNV) 和新型拷贝数变异 (CNV)。一名 6 岁男孩出现发育迟缓和动眼神经失用症。脑磁共振成像显示小脑间歇性轻度萎缩。血清甲胎蛋白水平在正常范围。进行了下一代测序和单核苷酸多态性阵列测试。下一代测序揭示了 ATM 中的杂合无义致病性变异，c.742C > T (p.Arg248Ter)，遗传自父亲。单核苷酸多态性芯片揭示了从母亲遗传的复合杂合CNV，arr[GRCh37] 11q22.3(10851766–108183226) × 1, 31460 bp（外显子24–40缺失ATM），并通过逆转录聚合酶验证链式反应分析（RT-PCR）。我们证明该变体 (NM_000051.4:c.3403_6006del) 生成 ATM 外显子 24-40 的框内删除产物 (p.Ser1135_Gln2002del)。涉及先前描述的致病性 SNV 和新型 CNV 的 ATM 变异的复合杂合性可能与非典型临床表现有关。 该临床报告扩展了非典型共济失调毛细血管扩张症中 ATM 致病性变异的遗传和表型谱，从而使常规下一代测序之外的高级分析的实施成为共济失调毛细血管扩张儿童诊断和康复服务的重要考虑因素。