P442: Macroglossia and elevated lactate as initial presenting features for cardiofaciocutaneous syndrome

Treatment and Management: Due to the infant's critical condition at birth, no active treatment was provided.Outcome and Follow-Up: The focus remained on supportive care and parental counseling after delivery.Discussion: MGS is classified as a ciliopathy, with its clinical features arising from disruptions in ciliary function.The patient was reported to be homozygous for a missense variant in the B9D1 gene (c.472G>A), which replaces valine with methionine at codon 158.This variant occurs at the last nucleotide of exon 6, part of the consensus splice site, and variants disrupting the splice site are known to cause aberrant splicing.Furthermore, this variant is absent in population databases like gnomAD.Given the alignment between the patient's phenotype and MGS, we propose this variant for further evaluation to support potential reclassification in the future.Conclusion: In summary, we present a patient with a clinical phenotype consistent with MGS who was found to be homozygous for an unreported missense variant in the B9D1 gene.We suggest that this variant should be reclassified as pathogenic based on its potential impact on gene function and its correlation with the clinical presentation.Our findings contribute to the growing body of knowledge surrounding Meckel-Gruber Syndrome and emphasize the importance of genetic analysis in identifying novel variants.Introduction: Meckel-Gruber Syndrome (MGS) is a rare, lethal autosomal recessive disorder characterized by significant genetic heterogeneity, with variants mapped to six distinct loci across different chromosomes.As a member of the ciliopathy group, MGS shares clinical features with conditions such as polycystic kidney disease, Joubert syndrome, and Bardet-Biedl syndrome.The pathophysiology is linked to variants in the B9D1 and B9D2 genes, which are critical for ciliary function and Hedgehog signaling pathways.Clinically, MGS is defined by a classic triad of occipital encephalocele, polycystic kidneys, and postaxial polydactyly, with associated anomalies including oral clefts, genital abnormalities, and central nervous system malformations.Cardiac defects may also occur.The reported prevalence of MGS ranges from 1 in 13,250 to 1 in 140,000 live births, with higher rates noted in populations of Finnish, Belgian, Bedouin, and Gujarati Indian descent.This report presents a patient whose phenotype aligns with the classic triad of MGS and who was found to be homozygous for a variant of uncertain significance (VUS) in the B9D1 gene (c.472G>A).Notably, this missense variant has not been previously documented in the literature.Case Presentation: The patient was a 2-hour-old male infant, born at 32 weeks of gestation, who exhibited multiple congenital anomalies and unfortunately passed away shortly after birth.The pregnancy was complicated by significant fetal findings, including a large posterior encephalocele measuring 2.8 x 3.3 x 2.8 cm, bilateral multicystic dysplastic kidneys, a small bladder, bilateral club feet, bilateral polydactyly of the feet, and bilateral bowed tibias measuring less than 1%.Additionally, the fetus presented with bilateral clenched hands, overlapping fingers, and a fixed left hand.The parents declined amniocentesis and chorionic villus sampling (CVS) during the pregnancy.Prenatal cell-free DNA screening indicated a low-risk male fetus, carrier screening revealed a variant of uncertain significance (VUS) in the B9D1 gene (c.472G>A) in both parents, associated with Meckel syndrome type 9.The family history included a 7-year-old daughter with developmental delay, autism, and epilepsy.The parents indicated that both their 6-year-old son and 9year-old daughter were healthy.The father reported that his mother had experienced five pregnancy losses, and notably, the parents are first cousins, with both paternal and maternal ancestries being South Asian.Dysmorphic features observed in the postmortem evaluation of the infant included a large posterior encephalocele, low anterior hairline, hypertelorism, underdeveloped left helix, overfolded right helix, a wide nasal base with a prominent bridge, a smooth philtrum, and a cleft palate.The abdomen was non distended but prominent, likely due to polycystic kidneys.The musculoskeletal assessment indicated an abnormal creasing pattern, postaxial polydactyly in all four extremities, contractures of the knees, and bilateral club feet.The infant was neurologically assessed as deceased.Diagnostic Workup: The carrier screening revealed a variant of uncertain significance (VUS) in the B9D1 gene (c.472G>A) in both parents.The family history included a 7-year-old daughter with developmental delay, autism, and epilepsy, while their other children were healthy.The father reported that his mother had experienced five pregnancy losses, and both parents are first cousins, with South Asian ancestry.After delivery, a Ciliopathies panel was ordered and reported this individual as homozygous for a likely pathogenic variant in the B9D1 gene.