Rapidly Progressive Infantile Dilated Cardiomyopathy in Long–Olsen–Distelmaier Syndrome Associated with RRAGC NM_022157.4:c.343T>C, p.(Trp115Arg): A Case Report

Figures

• 

  Figure 1. Simplified pedigree of the proband and parents. The proband was a male infant born to consanguineous, clinically unaffected parents and carried the heterozygous RRAGC NM_022157.4:c.343T>C, p.(Trp115Arg) variant. He presented with congenital lamellar cataracts, frontoparietal polymicrogyria, hypocalcemia with hyperphosphatemia, and rapidly progressive dilated cardiomyopathy at 53 days of age and died at approximately 2 months. The arrow identifies the proband, the diagonal line indicates death, and the double horizontal line denotes parental consanguinity. Open symbols indicate clinically unaffected parents, and the purple-filled square indicates the affected male proband. Parental segregation testing was unavailable; therefore, de novo or inherited status could not be established.

• 

  Figure 2. Clinical timeline of the present case. Timeline of a term male infant with early metabolic disturbance, cortical malformation, congenital cataracts, and preserved baseline ventricular function who developed fulminant dilated cardiomyopathy at 53 days of age during a rhinovirus/enterovirus-positive respiratory illness. Its causal contribution and the presence of myocarditis could not be established. Accordingly, the contemporaneous clinical WES record documented a heterozygous RRAGC c.343T>C, p.(Trp115Arg) variant, reported by the diagnostic laboratory as likely pathogenic and subsequently standardized in this manuscript as NM_022157.4:c.343T>C; published variant-specific evidence supports a gain-of-function mechanism consistent with the proposed unifying molecular diagnosis. Despite intensive care support, the infant developed refractory cardiogenic shock and died at approximately 2 months of age.

• 

  Figure 3. Homologous-site conservation and calibrated evidence for the RRAGC NM_022157.4:c.343T>C, p.(Trp115Arg) variant. (A) Full-length representative RRAGC orthologues and RagC/D co-orthologues were aligned using FAMSA. Human Trp115 was mapped to its homologous alignment column rather than compared at a fixed residue number. Tryptophan was present in five of six sequences, including all vertebrate RRAGC orthologues and Drosophila RagC-D, whereas Caenorhabditis elegans ragc-1 contained isoleucine; therefore, the site is strongly but not universally conserved. (B) The accompanying panel summarizes the variant-level evidence incorporated into the independent manuscript-level ACMG/AMP reassessment. Criterion-specific evidence, evidence strengths, supporting references, and point assignments are reported in the Results. Correlated computational predictors were not counted independently, and the panel should not be interpreted as a reconstruction of the diagnostic laboratory’s original classification.

• 

  Figure 4. Independent manuscript-level ACMG/AMP reassessment of the RRAGC NM_022157.4:c.343T>C, p.(Trp115Arg) variant. (A) Applied evidence categories and their assigned strengths. (B) Criteria considered but not applied because the required evidence was unavailable or insufficient. (C) Bayesian point-based synthesis. The core evidence yielded 6 points, supporting a likely pathogenic classification; inclusion of provisional PM6_Supporting increased the score to 7 points without changing the classification. Detailed criterion-specific rationale and supporting references are provided in the Results. This reassessment was performed independently of the diagnostic laboratory’s original classification.

• 

  Figure 5. Schematic structural context of Trp115 in the wild-type RagC nucleotide-binding domain. The location of the RRAGC NM_022157.4:c.343T>C, p.(Trp115Arg) variant site is illustrated with reference to the experimentally determined wild-type human RagC nucleotide-binding-domain structure, PDB 3LLU, solved by X-ray crystallography at 1.40 Å resolution in the presence of GNP and Mg2+. (A) Schematic representation of the region containing Trp115. β-strands are shown in blue, α-helical structure in magenta, and connecting loops in grey. Wild-type Trp115 is highlighted in red as the position affected by the p.(Trp115Arg) substitution. GNP, Mg2+, and selected residues are included for structural orientation and should not be interpreted as a coordinate-derived contact analysis. (B) Schematic representation of the central β-sheet register with reference to the deposited secondary-structure annotations for PDB 3LLU. Trp115 is located within the strand encompassing residues 112–116. The indicated Trp115–Leu66 relationship represents the reported backbone strand-register pairing; it does not establish that the p.(Trp115Arg) substitution disrupts this interaction. The deposited structure contains…