Background: 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.
Case presentation: 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.
Conclusions: 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.