Traditionally, clinicians relied on key phenotypic patterns for disease diagnosis. However, many patients do not fit into predefined categories and exhibit atypical features not observed in specific syndromic diagnoses. Next generation sequencing and clinical genomics have demonstrated that a significant subset of atypical presentations results from pathogenic variation in 2 or more genes causing “blended” phenotypes. As many as 3-7 % of molecularly diagnosed patients undergoing clinical exome sequencing carry 2 or more distinct molecular diagnoses with an even higher percentage in consanguineous populations.

We report a 9-month-old male with global developmental delay, epilepsy, brain abnormalities, severe hypotonia, dysmorphism, and musculoskeletal abnormalities born to consanguineous parents with a history of infertility. ES showed a total absence of heterozygosity of 431.2 Mb and revealed novel deleterious variants in ZC4H2 (c.526A>C:pN176H), MUSK (c.1493C>T:pA498V), CAPN3 (c.259C>G:pL87V), and NAV2 (c.1996G>A:pG666R). MUSK, CAPN3, and NAV2 map within an AOH interval of 10.4 Mb, 2.6 Mb, and 6.5 Mb, respectively, and ZC4H2 is located on the X chromosome and hemizygous. ZC4H2, MUSK, and CAPN3 are established disease genes linked to Wieacker-Wolff syndrome, congenital myasthenic syndrome, and limb-girdle muscular dystrophy, respectively. NAV2 is a novel disease gene candidate implicated in cerebellar dysgenesis in mouse models.

Multilocus variation is an emerging concept explaining atypical disease presentations.  We present a child with a complex blended phenotype resulting from  deleterious variants in 4 genes. Further studies in larger cohorts are needed to determine the exact incidence of multilocus variation across different populations with implications for disease management.