P427: Thirty-year odyssey to dual diagnoses: Value of longitudinal genetics follow-up

Outcome and Follow-Up: Information provided with the parental specimens indicated both parents had relevant clinical features.The proband's 21-year-old mother was listed as symptomatic and had congenital heart disease, required cardiac ablation with subsequent acquired heart block requiring pacemaker placement during pregnancy, learning challenges, vision issues, learning disability, and reportedly required special education.The proband's 25-year-old father was also listed as symptomatic with autism spectrum disorder/Asperger.Subsequent to the CMA results, the proband was noted to have additional features consistent with Cohen syndrome, including a prominent nose, laryngomalacia, and poor feeding.Discussion: Cohen syndrome was first described in the 1970s and over 200 patients have been reported in the literature since that time from a wide variety of ethnic groups but is overrepresented in the Finnish population due to founder variants.Literature suggests the disease is underdiagnosed and may be a common cause of idiopathic delays.The pathological mechanism of pathogenicity of VPS13B-related Cohen syndrome has not yet been determined, but the mechanism of disease appears to be biallelic loss-of-function.Heterozygotes are typically unaffected.In this case, both parents were described as symptomatic and presented with clinical features that may be unrelated to their carrier status. Conclusion:In conclusion, we present a proband with biallelic inheritance of overlapping deletions involving the VPS13B gene, leading to a diagnosis of autosomal recessive Cohen syndrome.This case underscores the diagnostic importance of considering copy number variants in VPS13B in suspected cases of Cohen syndrome.Despite the typical asymptomatic carrier status, both parents exhibited clinical features, suggesting potential phenotypic variability.This study highlights the need for increased awareness and consideration of such genetic variants in clinical diagnoses, which may contribute to better understanding and management of Cohen syndrome.Introduction: Cohen syndrome is a rare genetic disorder caused by biallelic pathogenic variants in the VPS13B gene.This condition is characterized by distinct dysmorphic features, microcephaly, truncal obesity, impaired intellectual development, progressive retinopathy, and intermittent congenital neutropenia.While the majority of variants reported are nonsense and frameshift mutations, copy number variants are estimated to account for approximately 30% of pathogenic VPS13B variants.We present an affected proband with biallelic inheritance from heterozygous parents of overlapping deletions at 8q22.2 including portions of the VPS13B gene, expected to result in a diagnosis of Cohen syndrome.Case Presentation: The proband is a newborn female, born via cesarean at 36 weeks 4 days gestation to a G1 P0 21-year-old mother.She was referred for clinical chromosomal microarray (CMA) studies due to multiple congenital anomalies, prematurity, concern for premature beats, dysmorphic features, ear malformation, bilateral club foot, down-slanting palpebral fissures, overlapping thumbs, small for gestational age, and persistent pulmonary hypertension of the newborn (PPHN).Junctional tachycardia was apparent at three weeks of age.Diagnostic Workup: Clinical CMA analysis revealed a complex pattern of contiguous deletions at 8q22.2, within the VPS13B gene (OMIM 607817; transcript NM_017890), consisting of a 114 kilobase single copy deletion including exons 7-17; an adjacent 29 kilobase region of homozygous deletion within intron 17; and a 555 kilobase single copy deletion including exons 18-44.Targeted parental CMA analysis demonstrated that the parents carry overlapping deletions in the 8q22.2region.A 584 kilobase deletion at 8q22.2 was inherited from the mother, and a 143 kilobase deletion at 8q22.2 was inherited from the father.The genomic regions of these two copy number variants overlap, resulting in a homozygous deletion for approximately 29 kilobases.