To model the recessive, presumed loss-of-function TAF1A mutations, stable knockout of the single taf1a zebrafish homolog was performed, resulting in a frameshift mutation leading to a premature stop codon (Supplementary Material, Fig. S2). Homozygous mutant zebrafish embryos recapitulated a heart failure phenotype beginning at 6 days post-fertilization, with progressive pericardial edema and a significant decrease in ventricular fractional shortening compared to WT embryos (Fig. 3A and B). Knockout of taf1a resulted in early lethality, with embryonic death occurring 6 to 11 days post-fertilization (Fig. 3C).

Nucleolar segregation was identified in approximately 50% of cardiomyocytes examined (Fig. 2J and K), together with cytoplasmic aggregates coinciding with sarcomere degeneration (Supplementary Material, Fig. S1). These gene-specific findings were absent in pediatric normal and DCM controls (Fig. 2H,I,K; Supplementary Material, Fig. S1).

Table 1Summary of TAF1A variants Gene Variant SIFT Score (11) SIFT Prediction PolyPhen2 Score (12) PolyPhen2 Prediction ExAC Allele Frequency (%) PhyloP Score (13) TAF1A L84S 0.0 Damaging 1.0 Probably Damaging 0.0041 0.000796 TAF1A G341R 0.3 Damaging 1.0 Probably Damaging 0.0033 0.002259 Gene Variant SIFT Score (11) SIFT Prediction PolyPhen2 Score (12) PolyPhen2 Prediction ExAC Allele Frequency (%) PhyloP Score (13) TAF1A L84S 0.0 Damaging 1.0 Probably Damaging 0.0041 0.000796 TAF1A G341R 0.3 Damaging 1.0 Probably Damaging 0.0033 0.002259 

Figure 1View largeDownload slideIdentification of recessive TAF1A mutations in a sibling pair with DCM. (A) Family pedigree. Square, male; circle, female; solid, affected; open, unaffected; black font, age at screening echocardiography; red font, age at diagnosis; arrow, proband. (B) An iterative filtering scheme of whole exome sequencing variant calls identified a single candidate gene, TAF1A. (C) Sanger sequencing verified compound heterozygous missense mutations. (D) Conservation of L84, G341, and surrounding residues.

c.1021G > A, p.G341R

c.251T > C, p.L84S

There is no history of heart failure in the extended family.

Following her sister’s diagnosis, a screening echocardiogram at 13 months of age revealed mild-moderate left atrial enlargement but normal left ventricular chamber size and systolic function (EF = 60%). A surveillance study at 2 6/12 years of age was diagnostic for DCM, with moderate LV enlargement, moderate-severe LV systolic dysfunction (EF = 27%), moderate mitral valve regurgitation, and severe left atrial enlargement.

An underlying cause for her DCM was not identified, despite an extensive diagnostic workup including metabolic testing, karyotyping, chromosomal microarray, and genetic testing with a 10-gene DCM panel.

Echocardiography revealed DCM with severe four-chamber enlargement and decreased left ventricular ejection fraction (EF = 20%; normal ≥50%) in the absence of symptoms or physical findings of heart failure.

Here, we report a unique family with DCM in a sibling pair, both of whom developed decompensated heart failure requiring cardiac transplantation by 3 years of age. Exome sequencing of the sibling-parent quartet uncovered compound heterozygous mutations in TAF1A, implicating an unsuspected candidate gene for DCM. Consistent with known TAF1A function, electron microscopy identified a gene-specific defect in cardiomyocyte nucleoli from explanted hearts, indicative of impaired ribosomal RNA (rRNA) synthesis. taf1a knockout in zebrafish recapitulated a lethal heart failure phenotype. These findings reveal ribosomopathy as a cause for early-onset heart failure.

The Leu249 residue (exon 7) is a pterin-binding residue in PAH.

IER3IP1

p.K329E

R53C

p.R17H