Nagy Orsolya, Kárteszi Judit, Elmont Beatrix, Ujfalusi Anikó
Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Hospital of Zala County, Zalaegerszeg, Hungary.
Front Pediatr. 2021 Aug 20;9:664548. doi: 10.3389/fped.2021.664548. eCollection 2021.
Pathogenic variants of gene were identified first as a monogenic cause of childhood apraxia of speech (CAS), a complex disease that is associated with an impairment of the precision and consistency of movements underlying speech, due to deficits in speech motor planning and programming. variants are heterogenous; single nucleotide variants and small insertions/deletions, intragenic and large-scale deletions, as well as disruptions by structural chromosomal aberrations and uniparental disomy of chromosome 7 are the most common types of mutations. -related speech and language disorders can be classified as "-only," wherein intragenic mutations result in haploinsufficiency of the gene, or "-plus" generated by structural genomic variants (i.e., translocation, microdeletion, etc.) and having more likely developmental and behavioral disturbances adjacent to speech and language impairment. The additional phenotypes are usually related to the disruption/deletion of multiple genes neighboring in the affected chromosomal region. We report the clinical and genetic findings in a family with four affected individuals having expressive speech impairment as the dominant symptom and additional mild dysmorphic features in three. A 7.87 Mb interstitial deletion of the 7q31.1q31.31 region was revealed by whole genome diagnostic microarray analysis in the proband. The gene deletion was confirmed by multiplex ligation-dependent probe amplification (MLPA), and all family members were screened by this targeted method. The deletion was detected in the mother and two siblings of the proband using MLPA. Higher resolution microarray was performed in all the affected individuals to refine the extent and breakpoints of the 7q31 deletion and to exclude other pathogenic copy number variants. To the best of our knowledge, there are only two family-studies reported to date with interstitial 7q31 deletion and showing the core phenotype of haploinsufficiency. Our study may contribute to a better understanding of the behavioral phenotype of disruptions and aid in the identification of such patients. We illustrate the importance of a targeted MLPA analysis suitable for the detection of deletion in selected cases with a specific phenotype of expressive speech disorder. The "phenotype first" and targeted diagnostic strategy can improve the diagnostic yield of speech disorders in the routine clinical practice.
基因的致病变异最初被确定为儿童言语失用症（CAS）的单基因病因，CAS是一种复杂疾病，与言语运动计划和编程缺陷导致的言语相关运动的精确性和一致性受损有关。变异是异质性的；单核苷酸变异和小插入/缺失、基因内和大规模缺失，以及染色体结构畸变和7号染色体单亲二体造成的破坏是最常见的突变类型。与基因相关的言语和语言障碍可分为“仅基因相关型”，即基因内突变导致该基因单倍剂量不足，或“基因相关附加型”，由结构基因组变异（如易位、微缺失等）产生，且在言语和语言障碍之外更可能伴有发育和行为障碍。额外的表型通常与受影响染色体区域中基因相邻的多个基因的破坏/缺失有关。我们报告了一个家族的临床和遗传发现，该家族中有四名受影响个体，以表达性言语障碍为主要症状，其中三名还有额外的轻度畸形特征。通过全基因组诊断微阵列分析在先证者中发现了7q31.1q31.31区域7.87 Mb的间质性缺失。通过多重连接依赖探针扩增（MLPA）证实了该基因缺失，并通过这种靶向方法对所有家庭成员进行了筛查。在先证者的母亲和两个兄弟姐妹中使用MLPA检测到了该缺失。对所有受影响个体进行了更高分辨率的微阵列分析，以细化7q31缺失的范围和断点，并排除其他致病性拷贝数变异。据我们所知，迄今为止仅报道了两项关于7q31间质性缺失的家族研究，显示了基因单倍剂量不足的核心表型。我们的研究可能有助于更好地理解基因破坏的行为表型，并有助于识别此类患者。我们阐述了适合在具有特定表达性言语障碍表型的选定病例中检测基因缺失的靶向MLPA分析的重要性。“表型优先”的靶向诊断策略可提高常规临床实践中言语障碍的诊断率。
