TBI Rehabilitation Center, National Traffic Injury Rehabilitation Hospital, Gyeonggi-do, Republic of Korea.
Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
BMC Med Genomics. 2021 Aug 17;14(1):204. doi: 10.1186/s12920-021-01053-3.
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.
共济失调毛细血管扩张症是一种罕见的常染色体隐性、神经退行性疾病，由 ATM 基因的改变引起。大多数 ATM 致病变体是移码或无义变体，预计会截断整个 ATM 蛋白。在此，我们报告了一例具有非典型表型的共济失调毛细血管扩张症患儿，该患儿被鉴定为两种 ATM 变体的复合杂合子，涉及先前描述的致病性单核苷酸变异 (SNV) 和新的拷贝数变异 (CNV)。
一名 6 岁男孩因发育迟缓伴眼球运动性失用症就诊。脑磁共振成像显示小脑轻度萎缩间隔性进展。血清甲胎蛋白水平正常。进行了下一代测序和单核苷酸多态性阵列测试。下一代测序显示 ATM 中的杂合无义致病性变体，c.742C>T (p.Arg248Ter) 从父亲遗传。单核苷酸多态性阵列显示复合杂合 CNV，arr[GRCh37]11q22.3(10851766-108183226)×1, 31460 bp（ATM 外显子 24-40 缺失）从母亲遗传，通过逆转录-聚合酶链反应分析 (RT-PCR) 得到验证。我们证明该变体 (NM_000051.4:c.3403_6006del) 产生 ATM 外显子 24-40 缺失的框内缺失产物（p.Ser1135_Gln2002del）。
ATM 变体的复合杂合性涉及先前描述的致病性 SNV 和新的 CNV 可能与非典型临床表现有关。本临床报告扩展了 ATM 致病变体在非典型共济失调毛细血管扩张症中的遗传和表型谱，因此，在诊断和康复服务中，除了常规的下一代测序外，实施高级分析也是一个重要的考虑因素。
