Blended Phenotype Involving FBN1 and Novel PIGL Variants of Uncertain Significance: A Prenatal Case Report.

内容摘要

Genetic disorders presenting during the prenatal period are often complex, with overlapping phenotypes that pose significant diagnostic challenges. The increasing use of advanced fetal imaging modalities such as targeted imaging for fetal anomalies and high-resolution ultrasonography has enabled early identification of structural anomalies suggestive of syndromic conditions. However, correlating radiological findings with underlying genetic alterations remains difficult, particularly when variants of uncertain significance (VUSs) are detected. A VUS classification means that there is insufficient or conflicting evidence regarding a molecular alteration's role in disease. VUSs are categorized by the American College of Medical Genetics and Genomics within a five-tier system that also includes pathogenic, likely pathogenic, likely benign, and benign variants. The clinical interpretation of VUS is a recognized limitation in prenatal genetics, as these variants lack sufficient evidence for definitive pathogenic or benign classification, yet may contribute to phenotypic variability. Disorders such as Marfan syndrome (MFS), acromicric dysplasia (ACMICD), and coloboma, heart defects, ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME) syndrome are genetically heterogeneous and share overlapping clinical features, complicating precise delineation. Furthermore, the absence of parental genotyping often restricts the assessment of de novo variants and allelic segregation. In such scenarios, integrating fetal imaging, genomic sequencing, and functional predictive scores becomes essential to guide counseling and management. Reporting novel and blended phenotypes with VUS contributes to the growing body of evidence, facilitating refinement of variant classification and aiding clinical decision-making in subsequent pregnancies. We hereby report a case of fetus purporting as a blended phenotype with multiple skeletal and cardiac defects that harbors a heterozygous VUS in the FBN1 gene and a novel, homozygous VUS in the PIGL gene. The index patient is a spontaneously aborted 21-week-old fetus of a nonconsanguineously married couple. Grossly, it had retrognathia, low-set ears, cleft palate, depressed nasal bridge, and short neck. Targeted anomaly scan at 20 weeks of gestation showed the possibility of short-limb dwarfism, skeletal dysplasia with narrow thorax likely to be lethal, short and broad neck, congenital cardiac anomaly (tetralogy of Fallot with pulmonary stenosis), bilateral gross hydronephrosis and hydroureter, absent nasal bone, flat midface, micrognathia, and low-set ears, dilated cisterna magna, vermian agenesis, and Blake's pouch cyst. The fetal whole-genome sequence was found to harbor an autosomal dominant, heterozygous VUS in the FBN1 gene at exon 18 associated with MFS and ACMICD. It also had an autosomal recessive homozygous VUS, possibly a mutational "hot spot" in the PIGL gene at exon 1 associated with CHIME syndrome. De novo status of the variants cannot be ascertained, as parental genotyping could not be performed. Postgenetic test counseling was performed for the couple and was informed of the chances of affection with the same in subsequent offsprings. Based on VUS, important clinical management decisions or prenatal diagnosis are not recommended unless strongly correlated with the phenotype. CHIME syndrome is known to be expressed in homozygosity, while the autosomally dominant FBN1 gene mutation can manifest in heterozygosity. The presence of VUS variants in this case provides a genotype-phenotypic correlation to say that the variants might be the disease-causing ones. In the absence of a parental genomic study, the chance of co-inheritance of the variants in successive pregnancies ranges from 25% to 100%. Prenatal testing options in future pregnancies may be considered. RésuméLes maladies génétiques survenant pendant la période prénatale sont souvent complexes, avec des phénotypes chevauchants qui posent d’importants défis diagnostiques. L’utilisation croissante de modalités d’imagerie fœtale avancées, telles que l’échographie ciblée pour les anomalies fœtales, a permis l’identification précoce d’anomalies structurelles suggestives de conditions syndromiques. Cependant, la corrélation des résultats radiologiques avec les altérations génétiques sous-jacentes reste difficile, en particulier lorsque des variants de signification incertaine (VUS) sont détectés. Nous rapportons ici un cas de fœtus présentant un phénotype mixte avec de multiples anomalies squelettiques et cardiaques, porteur d’un VUS hétérozygote dans le gène FBN1 et d’un nouveau VUS homozygote dans le gène PIGL. L’échographie ciblée à 20 semaines a montré la possibilité d’un nanisme micromélique, une dysplasie squelettique, une anomalie cardiaque congénitale (tétralogie de Fallot), et des anomalies cranio-faciales. En l’absence d’étude génomique parentale, le risque de co-héritage dans les grossesses ultérieures varie de 25% à 100%. Des options de test prénatal lors de futures grossesses peuvent être envisagées.