Key result
Pedigree whole exome sequencing revealed a novel compound heterozygous LDLR mutation along with APOB and EPHX2 variants in a family with familial hypercholesterolemia.
Case Report (n=4)
Whole exome sequencing identified complex polygenic variants in a familial hypercholesterolemia pedigree, highlighting its utility in diagnosis and prenatal counseling.
May inform complex FH diagnosis; leaves open validation of polygenic variants before counseling use.
RATIONALE: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder typically caused by low density lipoprotein receptor (LDLR) gene mutation. Herein, we reported a FH pedigree with polygenic variants: LDLR, apolipoprotein B (APOB), and epoxide hydrolase 2 (EPHX2). PATIENT CONCERNS: A 10-year-old boy mainly presented multiple skin xanthomas and hypercholesterolemia. His family visited our hospital and was performed with pedigree whole exome sequencing (WES) at 20 + 3 weeks gestation of the mother's second pregnancy. DIAGNOSES: Based on the clinical features and genetic analysis, the pedigree was diagnosed with familial hypercholesterolemia. INTERVENTIONS: After genetic counseling, the couple opted to continue the pregnancy. Treatment advice and follow-up were offered to them. OUTCOMES: A novel compound heterozygous LDLR mutation: c.1009G>T and c.68-2A>G, derived from his parents respectively was revealed through pedigree WES, meanwhile, a maternal APOB gene variant: c.1670A>G and a paternal EPHX2 gene variant: c.548 dup of the proband were found together. Furthermore, the same compound heterozygous LDLR mutation as his was confirmed in his sister without APOB and EPHX2 variants in her fetal stage. LESSONS: WES combined with clinical features is essential for the diagnosis of FH, however, prenatal genetic testing results might bring more challenges to prenatal genetic counseling. Furthermore, it is more important to provide the guidance and early intervention for such families in the long run.
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Han et al. (2023) conducted a case report in Familial hypercholesterolemia (n=4). Whole exome sequencing was evaluated on Identification of genetic variants. Pedigree whole exome sequencing revealed a novel compound heterozygous LDLR mutation along with APOB and EPHX2 variants in a family with familial hypercholesterolemia.
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