Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy

Figure 1. (A–C) Transthoracic echocardiography images of the JPH2-p,E641* homozygous variant-positive proband demonstrating a severely dilated left ventricle with reduced systolic function and D, 12-lead ECG demonstrating bi-atrial dilation, PR-prolongation, interventricular conduction delay, and T wave abnormalities.

Figure 2. (A) Family 1 pedigree of the JPH2-p.E641* homozygous variant-positive proband and extended kindred. Arrow denotes proband; gray fill, fetal loss; black fill, dilated cardiomyopathy; diagonal line, deceased. (B) Sanger sequence chromatograms depicted wild type JPH2 as well as JPH2-p.E641* heterozygous and homozygous sequencing. (C) Linear topology with protein functional domains of JPH2 are depicted with location of p.E641* variant (red line) in the divergent region.

Figure 3. Family 2 pedigree of the GME family with both consanguineous parents hosting heterozygous JPH2-p.E641* variants. Arrow denotes proband; gray fill, cardiac arrest; black fill, Ebstein anomaly with rapidly progressive dilated cardiomyopathy; diagonal line, deceased.

Figure 4. (A) Bar graph comparing the frequencies of rare JPH2 variants in ostensibly healthy individuals. The gnomAD cohort is broken down into 8 ethnic subgroups. GME Variome and Iranome represent 2 independent Middle Eastern cohorts. No fill, total frequency; tan, missense variant frequency; red, LOF variant frequency. Error bars denote 95% CI; *P < 0.05, **P < 0.001 compared to European (Non-Finnish). (B) Bar graph comparing the frequencies of JPH2 variants in a GME Healthy Cohort (GME Variome + Iranome), an ostensibly healthy population (gnomAD), a cohort of clinical WES referrals at Baylor College of Medicine (WES), a cohort of clinical WES referrals from Iran (WES-Iran), and a population of those diagnosed with HCM. Error bars denote 95% CI; *P < 0.05, **P < 0.001 compared to gnomAD.

Figure 5. Amino-acid level genetic variability analysis of JPH2. Functional domains of JPH2 are depicted. Ortholog identity map and prevalence of variants in healthy individuals (gnomAD) by amino acid are depicted with orange lines representing rolling averages. Amino acid positions containing radical variants found in ostensibly healthy individuals and disease-causing variants found in those with cardiomyopathies are depicted, with those in red representing variants identified in individuals from the Middle East. MORN, membrane occupation and recognition nexus domain; TM, Transmembrane domain. *MAF exceeding Y-axis.