Targeted next-generation sequencing identifies the disruption of the SHANK3 and RYR2 genes in a patient carrying a de novo t(1;22)(q43;q13.3) associated with signs of Phelan-McDermid syndrome.

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.