Miscarriage Re-Analysis — Physician Summary

Variants identified

Transcript NM_001384732.1 (MANE Select); the primary literature numbers these alleles NM_023073.3:c.493del and c.6354dup.

Reportable finding — clinical detail

Interpretation & recommendations

1. A prior carrier screen does not exclude this result — it reports parental carrier status, not the conceptus genotype. CPLANE1 is not in the ACMG Tier 3 set (Gregg et al., Genet Med 2021), commercial panel content varies by laboratory, and no professional-society guideline includes carrier screening in the evaluation of pregnancy loss.
2. Offer PGT-M for the two familial CPLANE1 variants if IVF is pursued — Reticular's Embryo Report Core can incorporate them. This finding is not on its own an indication for IVF.
3. Offer prenatal diagnosis in a spontaneous pregnancy — CVS or amniocentesis for the two familial variants, independent of sonographic findings. A result confirming both variants establishes affected status and does not predict demise; counsel both trajectories, pregnancy loss or a live-born child with Joubert syndrome, before the procedure.
4. Genetic counseling is included with this report and recommended before any reproductive decision; confirm both parental variants in a CLIA-certified laboratory if results will direct management. Patients schedule directly at cal.com/team/reticular-bio/free-counseling-session, and the counselor is available to the clinical team for case review.

Methods & limitations

Methods

1. Whole-genome sequencing (short-read, ≥30× mean coverage) of both partners, aligned to GRCh38; single-nucleotide and small insertion/deletion variants classified per ACMG/AMP 2015 criteria with ClinGen specifications and cross-checked against ClinVar.
2. Products-of-conception genotypes were taken from the clinic's existing SNP microarray (46,XY, euploid) and phased against both parental genomes to infer which parental haplotypes the conceptus inherited at the CPLANE1 locus.
3. Gene–disease validity from ClinGen (CPLANE1 — Joubert syndrome 17: Definitive, autosomal recessive, Syndromic Disorders GCEP 2022-05-20). ClinGen holds no gene-validity curation for any pregnancy-loss entity, for any gene; the first-trimester evidence is the products-of-conception cohorts in the references.

Limitations

• Emerging approach, not routine practice. Re-analysis of a pregnancy loss against parental genomes is not yet addressed by professional-society guidance.
• Platform dependence. The variants were not directly genotyped in the conceptus; its genotype is inferred from array marker density, informative markers and sample quality, and the reported phasing confidence reflects those inputs.
• Fetal phenotype not observed. The pregnancy ended before any fetal anatomic survey (ISUOG 2023; AIUM 2021), so absence of sonographic findings at this gestation neither supports nor argues against this interpretation.
• Penetrance is not absolute — a plausible cause, not a proven one. The cohort that reported biallelic CPLANE1 in first-trimester losses also reported a live-born child with Joubert syndrome carrying two pathogenic alleles (Bozhinovski et al. 2024); outcome appears allele-pair specific rather than gene specific.
• Evidence base. The CPLANE1 products-of-conception series are small, and the two North Macedonian cohorts share one founder allele enriched in families of Albanian ancestry, so their reported frequencies are not general-population rates.
• Other contributors are not evaluated. Uterine, endocrine, immune and thrombophilic causes of pregnancy loss are outside this test; polygenic scores are not reported.

References

1. ClinGen gene–disease validity — CPLANE1 and Joubert syndrome 17 (Definitive, autosomal recessive, Syndromic Disorders GCEP, 2022-05-20)
2. ClinVar VCV000157513 — NM_001384732.1(CPLANE1):c.493del (p.Ile165TyrfsTer17), Pathogenic
3. ClinVar VCV001202647 — NM_001384732.1(CPLANE1):c.6354dup (p.Ile2119TyrfsTer2), Pathogenic/Likely pathogenic
4. Bozhinovski et al. 2024, Balkan Med J 41:97 — biallelic CPLANE1 confirmed in five of 246 euploid products of conception from losses before 12 weeks; parental segregation by Sanger sequencing; placental histopathology showed no specific characteristics; founder allele enriched in families of Albanian ancestry, and one live-born child with Joubert syndrome carried a biallelic genotype
5. Bozhinovski et al. 2025, Balkan J Med Genet 28:5 — exome sequencing of 66 euploid products of conception at 6–12 weeks (mean 8.2); molecular diagnosis in 13 of 66 (19.7%); CPLANE1 was one of two genes with biallelic pathogenic variants in the prenatal or early-embryonic-lethality category, with biparental inheritance confirmed by parental testing
6. Arnadottir et al. 2025, Nature 642:672 — whole-genome sequencing of 467 pregnancy-loss trios, most losses in the first 12 weeks; compound-heterozygous CPLANE1 c.6354dup and c.493del in a euploid loss from a couple with three consecutive losses
7. Parisi & Glass — Joubert Syndrome, GeneReviews (NBK1325) — clinical spectrum and natural history of live-born Joubert syndrome; CPLANE1 is one of its established genes
8. ISUOG Practice Guidelines (updated) 2023, Ultrasound Obstet Gynecol 61:127 — the first-trimester fetal anatomy assessment is defined for 11+0 to 14+0 weeks
9. AIUM Practice Parameter 2021, J Ultrasound Med 40:E1 — the detailed first-trimester obstetric ultrasound examination is defined for 12+0 to 13+6 weeks
10. Aminbeidokhti et al. 2025 (preprint) — genome sequencing of euploid pregnancy losses in 118 families with unexplained recurrent loss (two or more chromosomally normal losses); a possible single-gene cause in 30/118 (25.4%), of which 21/118 (17.8%) were P/LP
11. Zhao et al. 2021, Genet Med — exome sequencing of 102 euploid products of conception
12. Gregg et al. 2021, Genet Med 23:1793 — ACMG practice resource, carrier screening for autosomal recessive and X-linked conditions; Tier 3 gene set; framed as preconception/prenatal reproductive risk assessment
13. Lazarin et al. 2017, Prenat Diagn 37:350 — SLOS carrier frequency vs observed births in 262,399 individuals; estimated 42–88% in utero mortality for biallelic DHCR7 (the panel's one quantified loss fraction)
14. Aminbeidokhti et al. 2024, Hum Genet 143:185 — candidate lethal genes; preconception carrier-screening panels currently lack miscarriage-related genes (29/138 genes on the ACMG list)

Appendix A — genes evaluated (750+ genes, by mechanism group)

719 genes listed across 10 groups. The two survival groups are the “Known” evidence tier of the published 934-entry Human Intolerome (RPLdb), split by the database's recorded timing of lethality; its Emerging and Candidate tiers are sequenced and reviewed but not listed individually. Infertility groups take ESHRE FeRGI genes with moderate-or-stronger gene–disease evidence (score ≥ 9 of 18). Each gene is listed once in its best-fitting group, except MSH4, STAG3, and SYCE1 (meiosis in both sexes). The 750+ total is cross-referenced against other laboratories' infertility panels.