It has been known for more than 30 years that balanced translocations, especially if de novo, can associate with congenital malformations and / or neurodevelopmental disorders, following the disruption of a disease gene or its cis-regulatory elements at one or both breakpoints. We describe a 10-year-old girl with a non-specific neurodevelopmental disorder characterized by moderate intellectual disability (ID), gross motor clumsiness, social and communication deficits. She carries a de novo reciprocal translocation between chromosomes 1q43 and 22q13.3, the latter suggesting the involvement of SHANK3. Indeed, its haploinsufficiency associates with Phelan-McDermid Syndrome, whose main symptoms are characterized by global developmental delay and absent or severely delayed expressive speech. A deep molecular approach, including next-generation sequencing of SHANK3 locus, allowed demonstrating the breakage of RYR2 and SHANK3 on the derivative chromosomes 1 and 22 respectively, and the formation of two fusion genes SHANK3-RYR2 and RYR2-SHANK3 with concomitant cryptic deletion of 3.6 and 4.1 kilobases at translocation junction of both derivatives chromosomes 22 and 1, respectively. Although the interruption of SHANK3 accounts for the patient’s psychomotor retardation and autism-like behavior, we do not exclude that the interruption of RYR2 may also have a role on her disorder, or result in further pathogenicity in the future. Indeed, RYR2 that has a well-established role in the etiology of two autosomal dominant adulthood cardiac disorders (#600996 and #604772) is also expressed in the brain (cerebellum, hippocampus, and cerebral cortex) and about half of RYR2 mutation carriers present late onset primary generalized epilepsy without cardiac arrhythmogenic disorders. Moreover, RYR2 variants have also been sporadically reported in individuals with early onset schizophrenia or ID, and its constraint values suggest intolerance to loss-of-function. This study not only confirms the usefulness of the molecular mapping of de novo balanced rearrangements in symptomatic individuals, but also underscores the need for long-term clinical evaluation of the patients, for better evaluating the pathogenicity of the chromosomal breakpoints.

中文翻译：

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靶向二代测序确定了携带与 Phelan-McDermid 综合征症状相关的从头 t(1;22)(q43;q13.3) 患者的 SHANK3 和 RYR2 基因的破坏。

30 多年来，在疾病基因或其顺式调节元件在一个或两个断点处被破坏后，平衡易位，尤其是从头开始，可能与先天性畸形和/或神经发育障碍有关。我们描述了一名 10 岁女孩，她患有非特异性神经发育障碍，其特征是中度智力障碍 (ID)、粗大运动笨拙、社交和沟通障碍。她携带染色体 1q43 和 22q13.3 之间的从头相互易位，后者表明 SHANK3 的参与。事实上，它的单倍体不足与 Phelan-McDermid 综合征有关，其主要症状是整体发育迟缓和缺乏或严重延迟的表达性言语。深入的分子方法，包括 SHANK3 基因座的下一代测序，可以证明 RYR2 和 SHANK3 分别在衍生染色体 1 和 22 上断裂，并形成两个融合基因 SHANK3-RYR2 和 RYR2-SHANK3，伴随着 3.6 和 4.1 kb 的隐性缺失两个衍生物染色体 22 和 1 的易位连接，分别。虽然 SHANK3 的中断解释了患者的精神运动迟缓和自闭症样行为，但我们不排除 RYR2 的中断也可能对她的疾病有影响，或在未来导致进一步的致病性。事实上，RYR2 在两种常染色体显性成年期心脏病（#600996 和 #604772）的病因学中具有公认的作用，它也在大脑（小脑、海马、和大脑皮层）和约一半的 RYR2 突变携带者呈现迟发性原发性全身性癫痫，而没有心律失常疾病。此外，在早发性精神分裂症或 ID 的个体中也偶有报道 RYR2 变体，其约束值表明对功能丧失的不耐受。该研究不仅证实了从头平衡重排在有症状个体中的分子图谱的有用性，而且强调了对患者进行长期临床评估的必要性，以更好地评估染色体断点的致病性。其约束值表明对功能丧失的不容忍。该研究不仅证实了从头平衡重排在有症状个体中的分子图谱的有用性，而且强调了对患者进行长期临床评估的必要性，以更好地评估染色体断点的致病性。其约束值表明对功能丧失的不容忍。该研究不仅证实了从头平衡重排在有症状个体中的分子图谱的有用性，而且强调了对患者进行长期临床评估的必要性，以更好地评估染色体断点的致病性。