Case#: 33 year-old female; first cardiologic evaluation at age 24 (LV wall thickness 13 mm); re-evaluated at 33 after recurrent palpitations
DiseaseAssertion: Noonan syndrome (PTPN11) with sarcomeric hypertrophic cardiomyopathy (MYBPC3); non-obstructive HCM, mild phenotype
FamilyInfo: Father carries the MYBPC3 c.1790G>A variant and has HCM; the PTPN11 variant was absent in both parents, consistent with de novo. Both parents and the proband's brothers underwent full cardiologic evaluation, no cardiovascular disease in the other family members. Parents declined genetic testing of the underage siblings. Grandparents (I-1, I-2) and II-2, II-3 have unknown phenotypes (pedigree Fig. 2).
ParentalTesting: Both parents genotyped for the two proband variants (Table 1). Father heterozygous for MYBPC3 c.1790G>A; neither parent carries PTPN11 c.1510A>G, supporting de novo status. Phase between the two variants therefore established as in trans (different genes).
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001962 (Palpitations); HP:0004322 (Short stature); HP:0000271 (Abnormality of the face); HP:0001647 (Hypertelorism); HP:0000508 (Ptosis)
CaseHPOFreeText: Regular psychophysical development. First echo at 24 showed mild increase in LV wall thickness (13 mm). At 33, presented with several episodes of palpitations; exam showed mild facial dysmorphisms (wide mouth, sloping forehead, prominent nasal bridge, prominent nose, low-set ears), short stature, and a systolic heart murmur. Echo: asymmetric LV hypertrophy, maximum wall thickness 16 mm at the anterior interventricular septum, mild mitral regurgitation, non-obstructive. No other cardiovascular signs.
CaseNotHPOs: HP:0001635 (Congestive heart failure); HP:0001650 (Aortic valve stenosis); HP:0001642 (Pulmonic stenosis); HP:0001250 (Seizure)
CaseNotHPOFreeText: No heart failure, no LV outflow obstruction, no pulmonary stenosis, no other congenital heart defect. No intellectual disability; psychophysical development was regular. No other signs of cardiovascular disease on examination.
CasePreviousTesting: NGS panel of 325 cardiomyopathy-associated genes (Supplementary Table S1); MAF threshold 5%; variants validated by Sanger sequencing; cascade testing restricted to the two proband variants.
Genotyping Method: NGS targeted panel (Maxwell 16 DNA extraction, Agilent Alyssa analysis, Illumina Variant Interpreter, in-house pipeline) with Sanger validation; parental Sanger genotyping for the same two variants.
FunctionalAnalysis: None performed by the authors. They cite prior HeLa cell work showing the MYBPC3 c.1790G>A change causes exon 18 inclusion in the transcript and an almost undetectable 248 bp product.
Variant 1: PTPN11 NM_002834.3:c.1510A>G (p.Met504Val); heterozygous missense; de novo; classified pathogenic, explains Noonan syndrome
ClinVar: Not stated in the paper; verify the current record before submitting.
CAID: Not reported.
gnomAD: Not reported in the paper; I have not checked gnomAD for this variant.
Variant 2: MYBPC3 NM_000256.3:c.1790G>A (p.Arg597Gln); heterozygous missense; exon 18, last nucleotide of the exon, affecting a highly conserved residue and causing a splicing variation; inherited from the father
ClinVar: Not stated in the paper; authors note it is classified pathogenic/likely pathogenic for HCM in several genetic databases.
CAID: Not reported.
gnomAD: Not reported in the paper
PMID: 32824488
Gene: MYBPC3
AdditionalInfo: Authors describe this as the first reported young adult with HCM and mild NS carrying variants in both PTPN11 and MYBPC3. Note the terminology problem: the abstract calls them "compound heterozygous," but the variants are in different genes on different chromosomes, so this is digenic (double heterozygosity), not compound heterozygosity. The authors argue the mild phenotype contrasts with the usual expectation that multiple sarcomeric hits worsen the disease, and that red flags justified the broad panel.