Preimplantation genetic testing for concurrent Meckel Syndrome and hereditary breast cancer in a Chinese family harboring a novel NPHP3 pathogenic variant and a canonical BRCA2 frameshift variant.

Meckel syndrome (MKS) is a lethal autosomal recessive disease with high phenotypic and genetic heterogeneity. Defects in NPHP3 cause MKS type 7. Herein, we report a case of a Chinese family with a newborn male proband presenting with occipital encephalocele and polycystic kidneys. Whole-exome sequencing was performed on genomic DNA extracted from peripheral blood. Potential variants were assessed for pathogenicity. Two compound heterozygous variants of NPHP3 (c. 950T>C, p. Phe317Ser, and c.2694-2_2694-1delAG) were identified, which were inherited from both parents, with c.950T>C representing a novel variant. Two BRCA2 variants (c.5576_5579delTTAA, p. Ile1859Lysfs*3, and c.9357A>C,p. Leu 3119 Phe) were identified, which were inherited from the father. After the proband was diagnosed with MKS7, the couple chose preimplantation genetic testing for monogenic disorders (PGT-M) to simultaneously prevent the transmission of NPHP3 and BRCA2 pathogenic variants, leading to a successful pregnancy. Our study expands the NPHP3 variant spectrum and contributes to the molecular diagnosis and genetic counseling of MKS. This case indicates that PGT-M is a viable option for NPHP3-related MKS and BRCA-positive patients to avoid transmission while maintaining their families. Successful application of PGT-M provides a potential approach for treating other monogenic diseases.