Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis

Abstract

Biallelic variants in inorganic pyrophosphatase 2 (PPA2) are known to cause infantile sudden cardiac failure (OMIM #617222), but relatively little is known about phenotypic variability of these patients prior to their death. We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited, pathogenic missense variant (c.514G > A; p.Glu172Lys) and a novel, maternally inherited missense variant of uncertain significance (c.442A > T; p.Thr148Ser). This report expands the presenting phenotype of patients with PPA2 variants. It also highlights the utility of dried blood spots for postmortem molecular diagnosis.

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families

“…2). Although a c.442A>T;p.(Thr148Ser) variant has been reported previously [5] as a VUS, another variant (c.443C>G) giving rise to the same amino acid substitution is found in our cohort. Functional studies presented here, relating to the impact of the p.Thr148Ser substitution upon PPA2 activity, provide further evidence of pathogenicity, with both variants being classified as likely pathogenic (Table 2).…”

“…Kaplan-Meier survival curves (Fig. 1b) generated using data from this study and from five previous reports [1][2][3][4][5] indicate two age groups with highest mortality: one major group represented by infants below the age of 2 years (n = 23 from this cohort and n = 41 when combined with previous reports) and in adolescence (n = 5 from this cohort and n = 7 combined with previous reports). Clinical presentations were consistent with those previously reported in the literature with either sudden cardiac arrest (15/28 individuals, including all five teenagers) or acute heart failure (13/28 individuals).…”

“…Of note, the most frequent pathogenic PPA2 variant is c.514G>A; p.(Glu172Lys), identified in 11 of the 20 families in our cohort, and has been reported in several families in previous studies. [1][2][3]5] Recombinant human PPA2 containing this variant displays a 90% reduction in enzyme activity. [1] This variant has a gnomAD allele frequency of 0.00053, and has never been seen in the homozygous state either in gnomAD or in patients documented in the literature.…”

“…Three further reports detailed two families affected by recurrence of sudden death in childhood with individuals harboring novel combinations of biallelic PPA2 variants [3,4] and an isolated case. [5] In the first study [3], which focused on identification of the genetic basis of 66 childhood-onset cardiomyopathies from Finland, the authors described two affected sibs who both died of dilated cardiomyopathy at 8 and 5 months of age. Necropsies reported dilation of the left ventricle, focal fibrosis, and inflammatory infiltrates with acute myocyte loss.…”

“…Autopsy performed in one child was noncontributive to determining etiology. A third study [5] reported a male who suffered from stridor due to vocal cord hypomotility and died of SUDI at 5 weeks of age. Necropsy showed no dilated or hypertrophic cardiomyopathy.…”