P698: Accurate genotyping of high homology HBA and SMN genes from whole exome sequencing

Methods: Real-time trend analysis of genetic test results recognized a potential pattern of MYH11 duplications in patients with aortopathy and/or connective tissue disorder indications, prompting systematic result review and case compilation.The electronic medical record application was queried for aortopathy-and connective tissue disorder-related multigene panels performed from July 2020 to present, the results of which were retrospectively reviewed.Results with MYH11 whole-gene duplications reported were compiled for the case series and those without were omitted.Cases satisfying the inclusion criterion were supplemented with demographic and clinical data via comprehensive chart review.Results: MYH11 duplications were reported in 4 patients: 2 unrelated males with aortopathy and 2 siblings with connective tissue atypices.The siblings were suspected to harbor a larger gain compatible with 16p13.11microduplication syndrome due to a concomitant partial ABCC6 duplication, which is also positioned at 16p13.11 just 292.5 kb distal to MYH11.A similar finding was not reported in either aortopathy patient.One underwent the same genetic interrogation as the siblings.The other underwent an alternate panel approach that did not interrogate additional genes in the 16p13.11region.Both unrelated males presented in the 5th decade with aortic root dilatation and type A thoracic aortic dissection.Chart review did not reveal an extracardiac phenotype, consistent with nonsyndromic TAAD.One man self-reported a family history of aortic aneurysm in his mother and maternal grandmother, consistent with autosomal dominant disease segregation.Of note, no variants were detected in any of the ClinGen Aortopathy Working Group-curated TAAD predisposition genes.Both siblings presented in the pediatric period.The brother presented as the index case with attention deficit-hyperactivity disorder, disruptive behavior disorder, myopia, Marfanoid habitus, joint hypermobility-flexibility, scoliosis, dorsal horizontal striae rubrae, pectus excavatum, mitral valve regurgitation, high-arched palate, and positive Steinberg and Walker-Murdoch signs.The sister exhibited a comparatively milder phenotype with only joint hypermobilityflexibility and braced thoracolumbar scoliosis.Their duplication was confirmed as non-paternal, implying maternal inheritance.Of note, their mother is diagnosed with schizophrenia and bipolar disorder.Conclusion: This case series adds to an emerging body of empirical and functional evidence that MYH11 overexpression may represent the underlying genetic etiology of some TAAD subtypes and the connective tissue disorder-specific features of 16p13.11microduplication syndrome.The absence of other wellestablished causative agents, compelling clinical correlation, and striking phenotypic overlap presented here support further consideration of a dosage-sensitive pathogenic mechanism.