Faculty of Medicine, Pediatric Department Division of Child Neurology, The University of Jordan, Jordan.
Faculty of Medicine, The University of Jordan, Jordan.
Clin Neurol Neurosurg. 2022 Jun;217:107271. doi: 10.1016/j.clineuro.2022.107271. Epub 2022 May 2.
Identify the genetic determinants of congenital muscle dystrophy (CMD) in Jordanian children.
This prospective study included patients suspected to have CMD. Singleton whole-exome sequencing (WES) was performed as the first-tier diagnostic test.
44 patients were included: 27 boys and 17 girls. Consanguinity was reported in 32/44 (72.7%) patients, and a positive family history in 16/44 (36.3%) patients. WES uncovered pathogenic/ likely pathogenic variants in 19/44 (43.1%) patients, variants of uncertain significance (VUS) and negative results were identified in 15/44 (34.0%) and 10/44 (22.7%) patients respectively. Variants related to CMD were identified in 23/44 (52.2%) patients; pathogenic /likely pathogenic variants were identified in 12/23 (52.1%) and VUS in 11/23 (47.8%). The most common genes were related to basal membrane/extracellular proteins followed by genes related to alpha‑dystroglycanopathies. We have identified a rare association of one family with one sibling affected by CMD and the other sibling with Duchenne muscle dystrophy. A history suggestive of perinatal insult was found in 6/23 (26.0%) patients necessitating a high index of suspicion as CMD may present as cerebral palsy mimickers.Several strong candidate VUSs were identified and need future second tier testing for confirmation. WES identified genes related to other neuromuscular and non neuromuscular disorders in 21/44 (47.7%) patients;7/21 were pathogenic/likely pathogenic and 14/21 (66.6%) were VUS.
In countries with limited resources singleton WES could be considered the first tier diagnostic test to limit costs.
鉴定约旦儿童先天性肌肉营养不良症（CMD）的遗传决定因素。
本前瞻性研究纳入了疑似患有 CMD 的患者。对 44 名患者进行了单核苷酸多态性全外显子组测序（WES）作为一线诊断检测。
44 名患者中，27 名男孩和 17 名女孩。32/44（72.7%）例患者有近亲婚配，16/44（36.3%）例患者有阳性家族史。WES 在 19/44（43.1%）例患者中发现了致病性/可能致病性变异，在 15/44（34.0%）例和 10/44（22.7%）例患者中发现了意义不明的变异（VUS）和阴性结果。在 23/44（52.2%）例患者中发现了与 CMD 相关的变异，在 12/23（52.1%）例患者中发现了致病性/可能致病性变异，在 11/23（47.8%）例患者中发现了 VUS。最常见的基因与基底膜/细胞外蛋白有关，其次是与α-肌营养不良蛋白相关的基因。我们发现了一个罕见的家族关联，一个兄弟姐妹患有 CMD，另一个兄弟姐妹患有杜氏肌营养不良症。在 6/23（26.0%）例患者中发现了提示围产期损伤的病史，因此需要高度怀疑 CMD 可能表现为脑瘫模仿者。在 21/44（47.7%）例患者中发现了与其他神经肌肉和非神经肌肉疾病相关的多个强候选 VUS；7/21 为致病性/可能致病性，14/21（66.6%）为 VUS。
在资源有限的国家，WES 可以作为一线诊断检测，以降低成本。
