PDF(Pubmed)
Abstract：
Ataxia-telangiectasia (AT) is a complex neurodegenerative disease with an increased risk for bone marrow failure and malignancy. AT is caused by biallelic loss of function variants in ATM, which encodes a phosphatidylinositol 3-kinase that responds to DNA damage. Herein, we report a child with progressive ataxia, chorea, and genome instability, highly suggestive of AT. The clinical ataxia gene panel identified a maternal heterozygous synonymous variant (NM_000051.3: c.2250G > A), previously described to result in exon 14 skipping. Subsequently, trio genome sequencing led to the identification of a novel deep intronic variant [NG_009830.1(NM_000051.3): c.1803-270T > G] inherited from the father. Transcript analyses revealed that c.1803-270T > G results in aberrant inclusion of 56 base pairs of intron 11. In silico tests predicted a premature stop codon as a consequence, suggesting non-functional ATM; and DNA repair analyses confirmed functional loss of ATM. Our findings highlight the power of genome sequencing, considering deep intronic variants in undiagnosed rare disease patients.
摘要：
共济失调毛细血管扩张症（AT）是一种复杂的神经退行性疾病，骨髓衰竭和恶性肿瘤的风险增加。AT是由ATM中功能变体的双等位基因丢失引起的，其编码响应DNA损伤的磷脂酰肌醇3-激酶。在这里，我们报告一个患有进行性共济失调的孩子，舞蹈病,和基因组不稳定，强烈暗示AT。临床共济失调基因小组确定了一个母系杂合同义变体(NM_000051.3:c.2250G>A)，先前描述导致外显子14跳跃。随后，三重基因组测序导致从父亲继承的新型深内含子变体[NG_009830.1(NM_000051.3):c.1803-270T>G]的鉴定。转录分析显示c.1803-270T>G导致异常包含内含子11的56个碱基对。在计算机模拟测试中预测了一个过早的终止密码子，提示非功能性ATM；DNA修复分析证实了ATM的功能丧失。我们的发现突出了基因组测序的力量，考虑未诊断的罕见疾病患者的深层内含子变异。
