Embryo Prioritization Report — Physician Summary

TUBB8 c.686T>C (p.Val229Ala) — heterozygous, PATHOGENIC

Detected in Embryo 7 · Maternal-effect / oocyte biology

Definitive riskoocyte/zygote/embryo maturation arrest

Gene function: TUBB8 encodes the β-tubulin isotype that forms the oocyte meiotic spindle. Pathogenic variants disrupt microtubule assembly and spindle function, impairing oocyte maturation, fertilization, and the embryo's first cleavage divisions.

Research evidence: TUBB8 variants were first described in dominant oocyte maturation arrest with functional microtubule disruption (Feng et al., NEJM 2016); later series broadened the phenotype to fertilization failure and pre-implantation embryonic arrest (Zheng et al., 2021). p.Val229Ala is recorded as pathogenic in ClinVar. TUBB8 is the most frequently implicated single gene in oocyte-maturation-arrest cohorts.

This cohort: A pathogenic TUBB8 variant was detected in a reproductive-biology gene with strong evidence for oocyte maturation problems and early embryo arrest. The finding informs prioritization and does not exclude transfer on its own.

TAZ (TAFAZZIN) c.646G>A (p.Gly216Arg) — hemizygous, PATHOGENIC

Detected in Embryo 2 · X-linked · one changed copy, inherited from the egg source

Moderate risk evidenceBarth syndrome (X-linked) — male fetal loss and stillbirth in family series

Gene function: TAZ (TAFAZZIN) encodes tafazzin, the cardiolipin-remodelling enzyme of the inner mitochondrial membrane. Loss of function causes Barth syndrome — dilated or non-compaction cardiomyopathy, skeletal myopathy, neutropenia and 3-methylglutaconic aciduria. X-linked recessive: males are affected, carrier females are unaffected.

Research evidence: c.646G>A (p.Gly216Arg) is recorded as pathogenic/likely pathogenic in ClinVar by multiple laboratories (Variation 426783). TAZ is on the Human Intolerome's Known-tier prenatal-lethal list, the panel's inclusion criterion for this gene group. In a UK cohort of 19 Barth kindreds, six showed male fetal loss, stillbirth or severe neonatal illness, with fetal cardiomyopathy and hydrops described (Steward et al., Prenat Diagn 2010). The syndrome is definitive; the fetal-loss association rests on family series — moderate evidence.

Why it is reported: Reported as the moderate-risk tier: a pathogenic X-linked variant inherited from the egg source, hemizygous in this male embryo, in a gene on the panel's pregnancy-survival list (Human Intolerome, Known tier, prenatal-lethal). The egg source is an unaffected carrier. It orders the embryo after embryos without a viability-gene finding and is not, on its own, a reason to set the embryo aside.

This cohort: A published TAZ variant was detected, inherited from the egg source. TAZ sits on the X chromosome and this embryo is male, so there is no second copy of the gene to make up for the change; families who carry it report more male pregnancy losses and stillbirths than expected. The finding informs prioritization and does not exclude transfer on its own.

Also relevant after birth: Barth syndrome (cardiomyopathy, neutropenia) in an affected male; cascade testing on the egg source's side.

DHCR7 c.964-1G>C — heterozygous carrier, PATHOGENIC

Detected in Embryo 4 · Autosomal recessive · one copy, from the sperm source

Carrier · no effect on this embryoSmith-Lemli-Opitz syndrome (autosomal recessive) — one copy has no effect

Gene function: DHCR7 encodes 7-dehydrocholesterol reductase, the final enzyme of cholesterol synthesis. Biallelic pathogenic variants cause Smith-Lemli-Opitz syndrome.

Variant: c.964-1G>C is the most common SLOS allele, recorded as pathogenic in ClinVar; carrier frequency is roughly 1 in 50 in people of European ancestry.

This cohort: No viability-gene risk was identified. This embryo carries one copy of a DHCR7 variant, inherited from the sperm source, with a normal copy alongside it — a carrier result, recorded for the child's future rather than for this transfer.

Carrier reporting: the egg source does not carry a DHCR7 variant, so no embryo in this cohort can be affected. If transferred, the future child is a healthy carrier; the result is relevant to that child's own reproductive planning in adulthood and to cascade testing on the sperm source's side.