RPL3L InitiativeFrom rare disease to real hope

Dilated cardiomyopathy, type 2D (CMD2D)

CMD2D (OMIM 619371) is a rare autosomal recessive cardiomyopathy caused by homozygous or compound heterozygous pathogenic variants in RPL3L. It is characterized by neonatal onset of severe dilated cardiomyopathy with rapid progression to cardiac decompensation and death unless the patient undergoes heart transplantation. Heterozygous carriers are unaffected.

Rare — but not hypothetical

Eleven affected families were confirmed as of the 2026 mechanism study (Murphy et al.), with additional case reports since — on the order of fifteen to twenty patients worldwide (Europe, the Americas, the Middle East, and Asia). Because the disease is so new to the literature, the true number of affected children is almost certainly higher: neonatal DCM is common, and RPL3L is not yet routinely tested in every workup.

Clinical presentation

Babies with CMD2D are typically born at term and appear well at birth. Within the first days to weeks of life they present with acute heart failure, often triggered by nothing more than the normal postnatal circulatory transition or a minor illness.

Frequently reported features

FeatureApproximate frequency in reported cases
Severe neonatal DCM with rapid decompensationAll reported patients
Mitral regurgitation~75%
ST-T abnormalities on ECG~75%
Tricuspid regurgitation~50%
Variable: VSD, PFO, pulmonary hypertension, RBBB, AV block, premature atrial contractionsSingle cases each

Typical admission findings

Differential diagnosis

Initial presentations are frequently misattributed to sepsis-induced cardiomyopathy or viral myocarditis. Reported cases were confirmed infection- and virology-negative. In any neonate with unexplained severe DCM, biallelic RPL3L variants should be considered, and rapid genetic testing (see below) should be pursued alongside standard workup.

Genetics

CMD2D is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in RPL3L. The reported spectrum is small — 14 alleles across 11 confirmed families, plus additional case reports — and includes:

Affected individuals typically carry one of two recurrent hotspot missense variants paired with a private (family-specific) allele. Parental carrier testing and genetic counseling are essential; one reported case involved a de novo variant on one allele. Beyond CMD2D, a RPL3L variant (p.Arg242Trp) has been reported in a child with catecholaminergic polymorphic ventricular tachycardia, suggesting the gene can contribute to a broader range of cardiac phenotypes.

Mechanism: a dual loss- and gain-of-function disease

The recessive inheritance pattern initially suggested simple loss of function — but the biology is more interesting, and more instructive for therapy:

The hotspot double hit

Hotspot RPL3L variants simultaneously (1) induce nucleolar protein aggregation and disrupt rRNA processing, blocking ribosome biogenesis, and (2) preserve RPL3L's role in repressing RPL3 mRNA via unproductive splicing, preventing the compensatory RPL3 upregulation seen in knockout models. The result is a combined loss-of-function and gain-of-function mechanism that the neonatal heart cannot survive.

This model — built from human genetics, patient tissues, and isogenic cell models — explains why severity depends on the specific allelic combination, and it points directly at a therapeutic hypothesis: restore or mimic the RPL3 compensation pathway.

Diagnosis & management

Diagnosis

Management

Key publications