Prenatal Diagnosis of a Fetus With Congenital Malformations Caused by Compound Heterozygous Mutations in FANCA: A Case Report and Literature Review.

BACKGROUND: Fanconi anemia (FA) is a rare autosomal recessive genetic disorder that typically presents with congenital malformations. The sites of these malformations exhibit significant clinical heterogeneity. To date, 22 FANC genes associated with FA have been identified; however, the relationship between pathogenic genotypes and the heterogeneity of clinical manifestations has yet to be systematically elucidated.

METHOD: We selected a family with ultrasound findings indicative of abnormal development in the upper limbs and kidneys of a fetus that presented at Shandong Provincial Maternal and Child Health Hospital on October 25, 2023. The fetus was conceived via in vitro fertilization and embryo transfer (IVF-ET), and whole exome sequencing (WES) was performed on both the fetus and its parents. Following the guidelines established by the American Society for Medical Genetics and Genomics (ACMG), we interpreted the clinical significance of the identified mutant gene loci. Sanger sequencing, chromosomal microarray analysis (CMA), and q-PCR were utilized for verification. To enhance the diagnostic foundation, fetal umbilical cord blood was collected for the diepoxybutane (DEB)-induced chromosome breakage test (CBT), and the percentage of aberrant cells was calculated. Additionally, we conducted a literature review of FA cases associated with congenital malformations, cataloging the locations of congenital malformations in FA patients resulting from various FANC gene mutations.

RESULT: WES revealed the presence of c.3989 T>C (p.Leu1330Pro) in the FANCA gene of the fetus. Additionally, a 62 kb fragment deletion was identified in the q24.3 region of chromosome 16, affecting exons 1 to 6 of the FANCA gene. Both mutations are novel and represent compound heterozygous mutations in the FANCA gene. According to the ACMG guidelines, the two variants were interpreted as variant of uncertain significance (VUS) (PM2_P + PP3_M) and likely pathogenic (PVS1 + PM2_P), respectively. The presence of this compound heterozygous mutation was confirmed through Sanger sequencing, CMA and q-PCR technology. The sequencing results indicated that the variations at both sites were inherited from the mother and father, respectively. DEB-induced CBT confirmed the cell phenotype associated with FA. Compared to the control group, fetal lymphocytes treated with DEB exhibited a significantly higher rate of chromosomal aberrations. We systematically investigated the potential associations between various mutant genotypes of the major FANC genes and congenital malformation phenotypes. This suggests that when fetal structural abnormalities, particularly those involving limb and kidney development, are detected during prenatal diagnosis, FA should be included in the differential diagnosis, and a comprehensive genetic assessment should be performed.

CONCLUSION: The compound heterozygous variations of the FANCA gene, specifically c.3989 T>C (p.Leu1330Pro) and g.89874677_89936688del may be the genetic cause of the structural malformations of the upper limbs and kidneys of the fetuses in this study. Our review of the literature identifies a range of congenital anomalies associated with various FANC genes. The limb and renal phenotypes observed in this case align with the commonly reported manifestations in patients with FANCA mutations, indicating a potential connection that merits further investigation. Based on the analysis of relevant deformity reports, deformities involving limbs, bones, the brain, the urinary system, etc. can all suggest FA.