Peripartum Cardiomyopathy Genetic Screening Protocol and Registry

Abstract

Background

Peripartum cardiomyopathy (PPCM) is a pregnancy-associated form of systolic heart failure with high prevalence and mortality worldwide. It occurs in 1:1800 to 1:3500 births in the United States and disproportionately affects women in the Gulf South. Louisiana has the highest maternal mortality rate in the United States, yet no prospective registry exists to investigate the genetic basis of perinatal cardiovascular disorders, creating an urgent need for genetic assessment.

Objectives

The objective of the study was to establish the first PPCM prospective whole-genome sequencing and registry with future expansion to other perinatal cardiovascular disorders.

Methods

The PERCVD (Perinatal-Related Cardiovascular Disorder) Trial is being conducted at Woman’s Hospital, Louisiana, in collaboration with The Lundquist Institute at Harbor-UCLA Medical Center. Individuals meeting PPCM-ESC 2019 diagnostic criteria (left ventricular ejection fraction <45% or fractional shortening <30% with chamber dilation, onset between the last month of pregnancy and five months postpartum) are enrolled in the study. Electronic informed consent is obtained through secure REDCap. Patients complete a virtual medical history visit, receive a kit for self-collected DNA, and complete health surveys. Genomic DNA extraction, whole-genome sequencing, and bioinformatic analysis will identify and annotate variants using American College of Medical Genetics and Genomics criteria. A PPCM genetic registry will catalog variant patterns to support future risk stratification.

Results

The PERCVD Trial is enrolling patients, and clinical outcome data are not available. This protocol details eligibility criteria, study workflows, genetic testing algorithms, and follow-up design.

Conclusions

This trial is the first structured PPCM genetic screening program in the Gulf that will support precision cardiovascular care in maternal populations.

Central Illustration

Peripartum cardiomyopathy (PPCM) is systolic heart failure induced by the extreme stresses that pregnancy places on the maternal heart with no targeted therapies available. It affects 1 in 2,230 births in the United States alone and approximately 1 in 1,000 births worldwide.¹ Mortality ranges from 2.4% to 6% within the first 6 postpartum months, driven by acute decompensated heart failure, comorbidities, and secondary cardiovascular complications.² Women of African-American descent carry a disproportionate burden of this devastating disease, exhibiting significantly higher incidence, slower myocardial recovery, and elevated complication rates relative to other backgrounds. This increase in disparity is not fully explained by traditional risk factor models alone.³ Many survivors require advanced heart failure therapies, prolonged mechanical support, or cardiac transplantation. Established risk factors include advanced maternal age, hypertensive disorders of pregnancy, and multifetal gestation.⁴

Diagnosis of PPCM relies on echocardiographic evidence of new-onset systolic dysfunction, defined by the European Society of Cardiology (ESC) as a left ventricular ejection fraction (LVEF) below 45% or fractional shortening below 30%, presenting from the last month of pregnancy through 5 months postpartum in the absence of any identifiable alternative causes.^5,6 The American Herat Association/American College of Cardiology guidelines extend this diagnostic window modestly beyond 5 months postpartum; because the 2 frameworks differ in their temporal boundaries, the governing diagnostic criteria must be specified for any clinical study. The PERCVD (Perinatal-Related Cardiovascular Disorders) Trial uses ESC 2019 criteria as the enrollment standard.

Although the overall pathophysiology of PPCM has not been fully elucidated, accumulating evidence supports a significant genetic component.⁷ Pathogenic (P) or likely pathogenic (LP) variants particularly truncating mutations or deleterious missense mutations in sarcomeric, desmosomal, and cytoskeletal genes including TTN, MYH7, MYBPC3, LMNA, DSP, FLNC, DES, VCL, BAG3, TNNC1, and TNNT2 have been identified in PPCM patients.7, 8, 9 These variants overlap substantially with those observed in familial dilated cardiomyopathy (DCM), strongly suggesting shared inherited susceptibility pathways.8, 9, 10, 11, 12 Despite the American Herat Association's endorsement of genetic screening in DCM and the recognized genetic overlap with PPCM, genetic counseling and testing for PPCM remain profoundly underutilized. Mechanistic studies in murine models have additionally implicated Stat3¹³, Ppargc1a,¹⁴ and Ptrh2¹⁵ as critical protective factors in the maternal heart under gestational stress; targeted deletion of each gene in dams recapitulates a PPCM phenotype, therefore identifying these genes as high-priority potential candidates for human variant analysis may provide novel targeted therapies for PPCM.

No published guidelines currently address genetic testing specifically in PPCM, and no structured genetic evaluation program exists for the PPCM population. This gap is particularly consequential in Louisiana, where the combination of elevated PPCM prevalence, high African-American patient representation, and limited access to genetic counseling services creates compounding barriers to precision cardiovascular care. The Woman’s Hospital in Baton Rouge serves as a demographically rich PPCM referral population center, making it a valuable site for prospective genetic registry in this disorder.

To address this critical gap, we developed the PERCVD trial, a prospective clinical protocol, designed to enroll up to 200 cases with a history of perinatal cardiovascular disease. The initial focus is on collecting buccal swab derived genomic DNA from PPCM patients and healthy controls for whole genome sequencing (WGS) analysis. The data will be analyzed in a comprehensive bioinformatics pipeline that integrates multimodal cardiac phenotyping. Future expansion of the trial will include other perinatal cardiovascular disorders, family-based co-segregation analysis to characterize variant phenotype associations and developing family counseling strategies. This manuscript presents the clinical rationale, study design, methodological framework, and implementation strategy of the PERCVD trial.

Methods

Study design

The PERCVD trial is a prospective observational protocol conducted at Woman's Hospital, Baton Rouge, Louisiana, in collaboration with The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California. The registry protocol was approved by the Woman’s Hospital Institutional Review Board (IRB) (Protocol RP-24-007; approval date: April 8, 2024). All participants provide electronic informed consent before enrollment, and study procedures are conducted in accordance with institutional ethical and Health Insurance Portability and Accountability Act (HIPAA) requirements.

Women with confirmed PPCM per ESC 2019 criteria are approached for enrollment following initial stabilization and provision of electronic consent (e-consent). The registry opened for enrollment in January 2024, and enrollment is anticipated to remain open through 2027, with genetic analyses conducted on a rolling basis as samples are received. The enrollment target of up to 200 cases was established based on annual PPCM case volume in Louisiana. With an enrollment window spanning 3 years (2024 through 2027), this target is operationally achievable. The registry was approved by the IRB at Woman’s Hospital (Protocol RP-24-007). No external sponsor funds the trial.

Eligibility criteria

The trial enrolls 2 distinct groups, cases that are defined as individuals with a current or prior history of PPCM, and controls, defined as individuals with a previous pregnancy resulting in a live birth without any history of perinatal cardiovascular complications. Enrollment is open to any adult woman aged 18 years or older provided the applicable diagnostic inclusion criteria is met. Special population (minors, prisoners, and non-English-speaking individuals) and patients with pre-existing structural heart disease or cardiomyopathy of any etiology before the index of pregnancy are excluded for both cases, and controls consistent with the ESC 2019 diagnostic requirement for PPCM. No prior genetic testing is considered or collected. Detailed eligibility criteria are provided in Table 1. PPCM is specifically defined by echocardiographic evidence of left ventricular systolic dysfunction (LVEF <45% or fractional shortening <30%) with chamber dilation (end-diastolic dimension >2.7 cm/m²), occurring between the last month of pregnancy and 5 months postpartum, in the absence of an identifiable pre-existing cause. For controls, a history of chronic hypertension or any hypertensive disorder of pregnancy is an exclusion criterion whereas gestational diabetes, infertility treatment, and prior miscarriage alone do not exclude control participation, Controls do not undergo cardiac imaging due to absence of any cardiovascular indicators. Eligibility determination is made by the site investigator within the Woman’s Research team. Supportive diagnostic criteria are defined by current American College of Obstetricians and Gynecologists criteria, and a full diagnostic framework is specified in Table 2.

Table 1.

Perinatal-Related Cardiovascular Disorder Registry Eligibility Criteria

Criteria	Cases (n = ≤200)	Controls (n = ≤200)
Inclusion criteria	History of perinatal-related cardiovascular disease meeting ESC 2019 PPCM criteria or ACOG criteria	Previous pregnancy resulting in a live birth
	Ability and willingness to provide electronic informed consent	Ability and willingness to provide electronic informed consent
		Gestational diabetes, infertility treatment history and prior miscarriages
	Adult woman aged 18 y or older	Adult woman aged 18 y or older
	Prior genetic done or not, no data are abstracted or act as criteria of ineligibility	Prior genetic done or not, no data is abstracted or act as criteria of ineligibility
Exclusion criteria	Special Population (minors, prisoners and non-English-speaking individuals) and pre-existing structural heart disease or cardiomyopathy of any etiology before index pregnancy	Pre-existing structural heart disease or cardiomyopathy of any etiology before the index pregnancy
		History of chronic hypertension or any hypertensive disorder of pregnancy

ACOG = American College of Obstetricians and Gynecologists; ESC = European Society of Cardiology; PPCM = peripartum cardiomyopathy.

Table 2.

Diagnostic Criteria for PPCM Within the PERCVD Registry

Criterion	Specification
Primary echocardiographic criterion (required)	LV systolic dysfunction: LVEF <45% or fractional shortening (FS) < 30%, AND chamber dilation (LV end-diastolic dimension [EDD] >2.7 cm/m2), demonstrated by echocardiography performed between the last month of pregnancy and 5 months postpartum
Supportive imaging	Cardiac MRI and/or chest X-ray and ECG showing cardiac dysfunction
Supportive biomarker	Elevated circulating BNP or NT-proBNP levels
Exclusion criteria	Pre-existing structural heart disease or cardiomyopathy of any etiology before the index pregnancy

BNP = B-type natriuretic peptide; ECG = electrocardiogram; LV = left ventricular; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; NT-proBNP = N-terminal pro–B-type natriuretic peptide; PERCVD = Perinatal-Related Cardiovascular Disorder; other abbreviation as in Table 1.

Recruitment and consent

Eligible individuals are identified through direct contact of current and prior patients of Woman’s Hospital with relevant diagnoses, permissible under a partial HIPAA authorization waiver granted by the IRB. Contact methods include text message, telephone, email, and postal mail. In addition, the registry is promoted through Woman’s Hospital’s website (via a secure REDCap enrollment link), institutional communications (newsletter, social media), and dissemination through private physicians. Individuals may self-refer via the publicly accessible REDCap link. All eligible individuals who express interest undergo a virtual study visit that includes electronic informed consent (e-consent), administered via the REDCap platform in accordance with Woman’s Hospital IRB policy and HIPAA requirements as conducted by the Woman’s Research team. The virtual visit also encompasses collection of obstetrical and medical history (including medication history and general pregnancy health) and orientation to the buccal swab collection procedure (Figure 1). E-consented participants subsequently receive a mailed buccal swab kit; to protect participant residential addresses and prevent sharing of protected health information outside Woman’s research team, kits are mailed by Woman’s research team and returned to Woman’s. Deidentified samples are then sent for WGS. Bioinformatics analysis and analysis report from The Lundquist Institute is then sent to hospital for the input into registry. Participants may alternatively complete the swab in person at Woman’s Hospital. Participation is voluntary, and withdrawal is permitted at any stage. As this is the first study involving a variant registry, PPCM gene variants are not yet identified in the Gulf South population. Therefore, co-segregation analysis for first-degree relatives, family screening and genetic counseling will be a part of the future expansion of PERCVD protocol (Central Illustration).

Figure 1.

Buccal Swab Collection and Sample Processing Workflow

(1) Patients will self-administer two buccal swabs by swabbing inner cheek for 15 seconds. (2-3) Swabs are sealed and returned to Woman’s Hospital. (4) De-identified samples are sent for WGS. (5-6) WGS and Bioinformatics analysis performed (7) Gene variants are identified by The Lundquist Institute and reported to the Woman’s Hospital (8) Data added to Perinatal-Related Cardiovascular Disorder Registry. WGS = whole genome sequencing. Created in BioRender, Matter M (2026), https://BioRender.com/iy7dtya.

Central Illustration.

The PERCVD Trial Protocol

Adult women with peripartum cardiomyopathy (PPCM), diagnosed per 2019 European Society of Cardiology (ESC) criteria, undergo a six-stage clinical and translational workflow. Clinical Assessment confirms PPCM enrollment via echocardiography, 12-lead electrocardiogram (ECG), and cardiac magnetic resonance imaging (MRI) when indicated. Genetic Assessment involves buccal swab collection, DNA extraction, and quality control (QC) before whole genome sequencing (WGS). Bioinformatics annotation is performed using Annotate Variation (ANNOVAR), Variant Effect Predictor (VEP), Combined Annotation Dependent Depletion (CADD), Polymorphism Phenotyping v2 (PolyPhen-2), Sorting Intolerant From Tolerant (SIFT), Genome Aggregation Database (gnomAD), and ClinVar. Variants are filtered through a tiered cardiomyopathy gene panel (tier 1A: established genes; tier 1B: emerging genes; tier 2: mouse knockout [KO] models; tier 3: discovery candidates), with pathogenic (P) or likely pathogenic (LP) variants confirmed by Sanger sequencing and quantitative polymerase chain reaction (qPCR). Outcomes leads to PPCM Genetic Registry through variant identification and bench validation. Future expansion of the protocol includes other perinatal cardiovascular disorders (inflammatory cardiomyopathy, preeclampsia-associated heart failure, metabolic cardiomyopathies), co-segregation analysis in first-degree relatives, and cascade screening with family counseling. Created in BioRender, Matter M (2026), https://BioRender.com/2fka95i.

Medical record abstraction and periodic health status monitoring

After enrollment and e-consent, medical records are abstracted directly by the Woman’s Hospital Research team and will be responsible for the receipt or transmission of data. No records are transferred outside the Hospital; abstraction occurs in-house with data entered directly into the REDCap platform behind institutional firewalls, accessible only through password protected login. Abstracted variables span 4 domains that include demographic, general and obstetric history, index pregnancy and delivery, and neonatal outcomes as specified in Table 3. Records are reviewed by the Woman's Research team to confirm diagnostic criteria are met and alternative etiologies are absent. This review is documented in REDCap under a dedicated eligibility verification field. Data are stored indefinitely although no hard copies are retained. Only deidentified data are shared with The Lundquist Institute collaborators via secure file transfer. Enrolled participants are contacted by the Woman’s Research team at approximately 6 months and at 1 year via a brief health status survey administered through REDCap. These surveys capture interval cardiovascular events, changes in medications, new diagnoses, and current pregnancy status, thereby enabling phenotypic tracking within the registry.

Table 3.

PERCVD Registry Medical Record Abstraction Variables

Domain	Variables
Demographic	Age; self-reported race/ethnicity; height; weight; BMI; marital status; insurance type; educational attainment; primary language; employment status; maternal zip code at delivery hospitalization
General and obstetric history	Smoking status and history; parity; chronic hypertension; diabetes; prior cesarean delivery; history of preterm birth; breastfeeding history; medication history
Index pregnancy and delivery	Singleton vs multiple gestation; estimated gestational age at delivery; delivery route; length of hospital stay; induction of labor (yes/no) and indication (elective vs medical); hypertensive disorder of pregnancy diagnosis; diabetes diagnosis; oligohydramnios (yes/no); polyhydramnios (yes/no); magnesium sulfate administration; cardiac imaging results; BNP/NT-proBNP at diagnosis
Neonatal	NICU admission (yes/no); length of NICU stay; birth weight (grams); 1- and 5-minute Apgar scores

BMI = body mass index; NICU = neonatal intensive care unit; other abbreviations as in Tables 1 and 2.

DNA extraction

Upon receipt of the returned buccal swabs, DNA is extracted using a standardized phenol-chloroform-isoamyl alcohol protocol. RNA will not be isolated from buccal swab samples. The complete extraction procedure, reagent specifications, and quality control steps are detailed in Table 4. Two buccal swabs are collected per participant with both sent for genomic DNA extraction (second swab serves a quality-control and confirmation of any variant). No sample will be Biobanked for this study. Extracted DNA is quantified by NanoDrop spectrophotometry and assessed for integrity by agarose gel electrophoresis before submission. Deidentified samples, meeting quality thresholds, are outsourced to a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory for WGS and Sanger sequencing.

Table 4.

Buccal Swab DNA Extraction Protocol

Step	Procedure
Sample collection	Buccal mucosa swabbed bilaterally for 15 seconds per side following 30-second water mouth rinse; 2 samples collected into DNA Shield tubes (Zymo Research)
Lysis	Suspension in 500 μL lysis buffer (10 mM Tris pH 8.0, 10 mM EDTA, 2.0% sodium dodecyl sulfate (SDS) + 50 μL 10% SDS + 5–10 μL proteinase K (20 mg/mL); incubation at 56 °C for 1–3 h until complete dissolution
Phase extraction	Equal-volume phenol:chloroform:isoamyl alcohol (25:24:1) extraction; gentle inversion 3 min; centrifugation 10,000 × g, 4 °C, 10 min; upper aqueous phase recovered
RNA removal	RNase A (10 μL of 10 mg/mL) added; incubation 37 °C, 30 min; chloroform:isoamyl alcohol back-extraction; centrifugation 10,000 × g, 4 °C, 10 min
Precipitation	Double volume chilled isopropanol (Merck) + 1/10 volume 3 M sodium acetate; −20 °C for 1 h; centrifugation 10,000 × g, 4 °C, 10 min; pellet washed with 250 μL 70% ethanol; centrifugation 10,000 rpm, 10 min
Resuspension and storage	Air-dried pellet resuspended in 50 μL nuclease-free water or Tris EDTA buffer (10 mM Tris-HCl, 1 mM EDTA, pH 7.6); stored at −20 °C or −80 °C; shipped for WGS
Quality control	NanoDrop spectrophotometry (A260/A280 and A260/A230 ratios); agarose gel electrophoresis for integrity assessment before library preparation

WGS = whole genome sequencing.

Whole genome sequencing

Deidentified samples of PPCM patients and controls are sent for WGS. WGS is performed using polymerase chain reaction–free library preparation to minimize amplification bias, targeting a minimum mean genome-wide coverage of ≥30× across ≥95% of the GRCh38/hg38 reference genome. Unlike exome-based approaches, WGS requires no target capture step, providing uniform coverage of coding regions, intronic splice sites, regulatory elements, and structural variants (SVs). Sequencing is performed on DNBSEQ or equivalent short-read platforms.

Data analysis

RAW sequencing reads in FASTQ format as obtained from DNA samples will undergo quality check and be aligned to reference human Genome Burrow-Wheeler Aligner. Insertions/deletions (indels) will be identified using Genome Analysis Toolkit. To capture the large scale genomic rearrangements, SVs will be detected. For functional annotation, Annotate Variation, and Ensembl variant effect predictor will be used. Extracted variants will be cross-referenced against Genome Aggregation database for population frequency filtering. Variant pathogenicity will be prioritized based on Combined annotation Dependent Depletion Scores and will be classified in accordance with the American College of Medical Genetics and Genomics/Association for Molecular pathology guidelines. These analyses are based on the DNA extracted from buccal swabs for WGS and in this protocol Genome-wide association study will not be performed. The complete analysis plan with tools, versions, and thresholds is summarized in Table 5.

Table 5.

The PERCVD Registry Data Analysis

Analysis	Method	Parameters
Raw data quality control	FastQC	Check Phred quality scores, total read counts.
Alignment and preprocessing	BWA-MEM (or DRAGEN) to map reads to GRCh38 reference genome	Alignment rate >95%; (mean genome-wide target coverage >30 times); duplication rate <5%.
Variant calling (germline)	GATK or Deep Variant to detect single nucleotide variants (SNVs) and insertions and deletions (Indels).	Variant Quality Score Recalibration (VQSR) or hard filtering (e.g., quality by depth <2.0, FS >60.0).
Structural variant (SV) calling	Manta, Delly, or Genomic Rearrangement identification Software Suite (GRIDSS)	Size filtering (variants >50 bp); filter by paired-end and split-read support.
Variant annotation	ANNOVAR, Ensembl VEP	Functional consequences (missense, nonsense, frameshift, intronic, intergenic splice site).
Variant interpretation (WGS)	GATK v4.4.0 best-practice pipeline; ANNOVAR + Ensembl VEP; ACMG/AMP classification; gnomAD v3.1.2 MAF filtering (by global and regional populations)	SNV: CADD ≥20; INDEL: CADD ≥10; MAF ≤0.01 overall

ACMG/AMP = American College of Medical Genetics and Genomics/ Association for Molecular pathology; ANNOVAR = Annotate Variation; BWA-MEM = Burrow-Wheeler Aligner Maximal Exact Match; CADD = Combined Annotation Dependent Depletion; FS = fractional shortening; GATK = Genome Analysis Toolkit; gnomAD = Genome Aggregation Database; VEP = Variant Effect Predictor; other abbreviation as in Table 2.

Tiered cardiomyopathy gene panel filtering

Variants are filtered through a three-tiered cardiomyopathy gene panel, summarized in Table 6, which represents the locked reference panel for this trial. Tier 1A comprises genes with definitive or strong evidence for DCM/PPCM causality per ClinGen curation. Tier 1B comprises genes with emerging evidence. Tier 2 comprises genes identified as mechanistically critical in murine PPCM models (Stat3, Ppargc1a, Ptrh2). Tier 3 designates discovery-phase novel loci identified through hypothesis-free whole exome sequencing analysis. This tiered framework is fixed for the duration of the trial; deviations require prospective amendment.

Table 6.

The PERCVD Trial Tiered Cardiomyopathy Gene Panel

Tier	Gene	Protein Function	PPCM/DCM Evidence	ClinGen DCM Classification	Mouse PPCM Model	Ref. #
1A: Established	Ttn	Sarcomere scaffold	Strong	Definitive	Yes	7,8,9,10,11
	Lmna	Nuclear envelope	Strong	Definitive	Yes	7,8,9,11
	Myh7	Sarcomere motor	Strong	Definitive	Yes	7,11
	Mybpc3	Myosin binding	Strong	Definitive	Yes	11
	Scn5a	Sodium channel	Moderate	Moderate	No	11
	Rbm20	RNA splicing	Strong	Definitive	Yes	11
	Pln	SR calcium regulation	Strong	Definitive	Yes	11
1B: Emerging	Dsp	Desmosome	Moderate	Strong	No	11
	Flnc	Cytoskeleton	Moderate	Strong	No	11
	Bag3	Chaperone	Moderate	Strong	Yes	11
	Des	Intermediate filament	Moderate	Strong	Yes	11
	Vcl	Costamere	Moderate	Moderate	Yes	11
	Tnnc1	Troponin C	Moderate	Moderate	No	11
	Tnnt2	Troponin T	Moderate	Definitive	No	11
	Nexn	Z-disc	Moderate	Moderate	Yes	11
2: Preclinical mouse models	Stat3	JAK/STAT signaling	Mechanistic	Limited	Yes (KO)	13
	Ppargc1a	Mitochondrial biogenesis	Mechanistic	Limited	Yes (KO)	14
	Ptrh2	Mitochondria-associated peptidase; mediates integrin-regulated cardiomyocyte survival and apoptosis (Bit-1/BIT1)	Mechanistic	Limited	Yes (KO)	15
3: Discovery	Novel loci	To be determined	Hypothesis	None	N/A	N/A

DCM = dilated cardiomyopathy; KO = knockout; N/A = not applicable; other abbreviation as in Tables 1 and 2.

Primary and secondary endpoints

The primary endpoint is to identify PPCM patients with at least 1 P or LP variant identified in Tier 1 cardiomyopathy genes via WGS within the 6-month postenrollment analysis window. Follow-up extends to 12 months of postenrollment to capture LVEF recovery trajectories and enable variants of uncertain significance (VUS) reclassification over time (summarized in Table 7).

Table 7.

The PERCVD Trial Endpoints

Endpoint	Definition	Assessment Window
Primary	Proportion of enrolled PPCM patients with ≥1 pathogenic (P) or likely pathogenic (LP) variant in Tier 1 cardiomyopathy genes via WGS	6 mo postenrollment
Secondary 1	Co-segregation confirmation rate of P/LP variants in first-degree relatives	12 mo
Secondary 2	Rate of VUS reclassification to P/LP or benign	12 mo
Secondary 3	Association between variant carrier status and LVEF recovery	6 mo postpartum
Secondary 4	Frequency distribution of variants across three gene tiers	End of study
Secondary 5	Proportion with variants in STAT3, PPARGC1A, or PTRH2	End of study
Secondary 6	Variant concordance rate between WGS and Sanger/qPCR confirmation	6 mo

P/LP = pathogenic/likely pathogenic; qPCR = quantitative polymerase chain reaction; VUS = variant of uncertain significance; other abbreviation as in Tables 1, 2, and 4.

Return of result

VUS are communicated with appropriate context and are tracked longitudinally for potential reclassification. No results are returned to participants without clinical oversight. However, the current PERCVD study represents a pilot initiative, and due to funding limitations, accredited genetic counselors were not integrated into the program at this stage. As the trial expands, incorporation of certified genetic counselors will be a key priority, given their essential role in interpretation of genetic findings, and informed clinical decision-making.

PPCM genetic registry

All genetic, clinical, and imaging data are entered into a secure, institutional HIPAA-compliant genetic registry with restricted-access governance. The registry enables long-term longitudinal tracking of variant classifications, VUS reclassification events, LVEF recovery trajectories, and identification of population-specific variant patterns in the Gulf South PPCM population. Deidentified data will be submitted to ClinVar to contribute to international variant databases. The registry is designed to serve as a scalable resource for future multisite expansion.

Co-segregation analysis

Woman’s Research team does not contact first-degree relatives directly. Instead, it is up to the will of the proband/individual to share consent information and results with their relatives. Contact is only initiated by the study team if a relative actively reaches out and expresses independent interest. Once contact is established, their independent informed consent is obtained and documented within REDCap. Three-generation pedigrees will be constructed using standardized pedigree nomenclature to assess inheritance patterns and penetrance, with future expansion planned to include additional perinatal cardiovascular disorders, family screening, co-segregation analysis, and genetic counseling.

Results

The PERCVD Registry is a prospective protocol currently open for enrollment. Enrollment commenced in January 2024, and the registry is designed to remain open through 2027 with target case enrollment of up to 200 individuals with PPCM and 200 controls. Enrollment is ongoing; genomic analyses are conducted on a rolling basis as samples are received. No aggregate genomic or clinical outcome data are yet available for reporting.

Discussion

The PERCVD registry addresses a key unmet clinical need of a prospective, WGS-based genetic registry for perinatal cardiovascular disorders in a high burden Gulf South population, with a hypothesis-driven focus on identifying gene mutations leading to PPCM susceptibility. To our knowledge, this is the first such registry established for this susceptible population. A distinctive feature of the PERCVD protocol is its inclusion of tier 2 genes derived from murine preclinical PPCM mouse models that include Stat3, Ppargc1A, and Ptrh2. Targeted deletion of Stat3, in mouse cardiac tissue produces a PPCM-like phenotype mediated through prolactin pathway dysregulation.¹³ Deletion of Ppargc1a reiterates peripartum ventricular dysfunction through mitochondrial biogenesis failure.¹⁴ More recently, a cardiac specific Ptrh2 deletion in dams recapitulates PPCM and identified high levels of cardiomyocyte apoptosis as a key component of the PPCM disease mechanism.¹⁵ Whether human variants in these genes contribute to PPCM susceptibility in a clinical population has not been fully investigated; the PERCVD Trial is designed to generate the first hypothesis-testing data to address this question. Confirmatory variant function studies in model systems are anticipated as a downstream application of registry-derived candidate variants.

WGS over exome sequencing is scientifically justified as prior PPCM genetic studies used WGS and reported P or LP variant yields of 15% to 26%, predominantly in sarcomeric genes such as TTN, consistent with an updated evidence assessment (doi: https://doi.org/10.64898/2026.03.09.26347990) with the majority of studies conducted in European-ancestry cohorts.¹⁶ WGS subsumes all exome coverage while additionally interrogating noncoding regulatory regions, intronic splice sites, and structural variants inaccessible to exome capture approaches. This is particularly relevant for PTRH2 where it has been reported that 2 PPCM patient heart tissues had RNA and protein down-regulated compared to control heart tissues suggesting potential variants which may include splice-site or regulatory alterations not captured by exome sequencing.¹⁵

The PERCVD registry’s multidisciplinary design pairing WGS with structured clinical phenotyping, medical record abstraction, and longitudinal health surveillance positions it to generate more than variant frequency data. The inclusion of controls without perinatal cardiovascular disease enables genuine case-control comparisons of variant burden and candidate gene enrichment, an analytical design absent from prior PPCM genetic studies that were predominantly uncontrolled case series.

Woman’s Hospital is a particularly important site for this registry. The institution serves the Louisiana Gulf South, which has the highest maternal mortality rate with the greatest PPCM burden yet remain the least genetically characterized group in cardiovascular genomics. The decentralized, e-consent and mail-based enrollment model reduces participation barriers for this population, which may face transportation, employment, and childcare constraints precluding traditional in-person research participation. This design also protects residential address confidentiality by ensuring that identifying information remains within the Woman’s Hospital system. The PERCVD trial also provides the first evidence base for genotype guided surveillance in PPCM, with direct implications for subsequent pregnancy and development of family counseling.

Study Limitations

Limitations of the PERCVD registry are acknowledged. The enrollment of 200 cases by 2027 represents a modest cohort. Although adequate for initial hypothesis testing regarding PTRH2 variant prevalence, statistical power for the association between genetic variants and clinical outcomes will depend heavily on the final sample size and the completeness of available medical records. Single-center registry findings may not generalize to PPCM populations in other geographic or demographic contexts, although the concentration of the highest burden population in a single institution is both a recruitment advantage and a potential source of ascertainment bias. Furthermore, WGS provides comprehensive genome wide coverage, interpretation of noncoding regulatory variants detected by WGS remains challenging given limitations in functional annotation of the noncoding genome; the analysis plan therefore prioritizes coding and canonical splice-site variants with American College of Medical Genetics and Genomics/Association for Molecular pathology classification as the primary interpretive layer. Another limitation is with the buccal swab derived DNA, although adequate for WGS, may yield lower quantity and quality than blood-derived DNA for some participants, potentially requiring reswabbing. Self-administered buccal swab collection introduces the possibility of inadequate sample collection, mitigated by clear written instructions. Also, the study materials are currently available in English only, excluding non-English-speaking individuals, most consequentially Spanish speakers who represent a meaningful and growing proportion of the Louisiana maternal population; this is recognized as a priority for future protocol amendment. Lastly, as a pilot initiative, the PERCVD program did not permit incorporation of dedicated genetic counseling services at this stage due to funding constraints. Recognizing the growing importance of genetic evaluation in cardiovascular care, the inclusion of accredited genetic counselors is a key objective for future expansion of the program.

Conclusions

Although the initial phase of the PERCVD trial and registry is the first prospective WGS-based genetic registry for PPCM in the Gulf South. We perceive findings from this registry have the potential to identify novel genetic determinants of perinatal cardiac vulnerability, validate several genes including PTRH2, STAT3, and PPARGC1A as human PPCM susceptibility genes, and mechanistically provide potential targeted therapeutic approaches for affected women and their families. The deep clinical and molecular data generated from this initial cohort will provide critical insights to facilitate expansion to include broader perinatal cardiovascular phenotypes. Subsequently, the PERCVD program will prioritize embedding accredited genetic counselors to translate complex clinical findings for patients and relatives, leading family education, and supporting cascade screening strategies.

Perspectives.

COMPETENCY IN MEDICAL KNOWLEDGE: Identified PPCM gene variants will establish first ever PPCM Genetic Registry.

COMPETENCY IN PATIENT CARE: Novel genetic drivers and validated risk genes will enable mechanistic, targeted PPCM therapies.

TRANSLATIONAL OUTLOOK: Genotype-phenotype relationships will provide clinicians an immediate blueprint for identifying susceptible patients.

Future studies should expand genetic profiling across perinatal cardiovascular diseases.

Funding support and author disclosures

This work was funded by an internal grant from The Lundquist Institute (to Dr Matter). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.