Guillouet-Gordon Syndrome With Severe Microtia in an Infant With a Homozygous Variant in MED16

Bi-allelic MED16 variants underlie the recently described MEDopathy termed Guillouet-Gordon syndrome (GGNS, MIM #621220), characterized by neurodevelopmental and structural anomalies. To date, 27 individuals with GGNS have been reported, collectively harboring 28 distinct compound heterozygous or homozygous MED16 variants. Here we present a male infant, born to unrelated parents, presenting with multiple congenital anomalies overlapping with the established GGNS phenotypic spectrum. Specifically, the clinical presentation included structural brain defects and neurodevelopmental deficits alongside significant craniofacial (microretrognathia, cleft palate, auricular/nasal features), cardiac (double outlet right ventricle), renal (horseshoe kidney), ocular (colobomatous microphthalmia), and hand/foot (syndactyly, nail hypoplasia) anomalies, fetal growth restriction, neonatal respiratory distress, and premature death in the first month of life. Notably, while different outer ear anomalies have been previously described in GGNS, the severe bilateral microtia and post-auricular skin tag identified in this individual extend the known clinical spectrum of the syndrome. Trio exome analysis identified a novel likely pathogenic homozygous missense variant in MED16, c.1573C>T p.(Arg525Trp). The p.(Arg525Trp) variant shows a relatively high population frequency (0.00025 in gnomAD v4.1), with no homozygotes identified to date. The elevated carrier frequency of this and other MED16 variants suggests a potential role in additional individuals with unexplained multiple congenital anomalies.