EOGT – Autosomal-Recessive Adams-Oliver Syndrome

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD), with variable central nervous system, cardiac, renal, and ophthalmological involvement. Both autosomal-dominant and autosomal-recessive forms are described, the latter due to biallelic mutations in DOCK6 or EOGT. EOGT encodes an endoplasmic reticulum-resident EGF-domain-specific O-GlcNAc transferase essential for proper O-Glycosylation of extracellular EGF-repeat proteins, including Notch receptors.

Six probands from five unrelated consanguineous families with homozygous EOGT variants including c.1013dupA (p.Asn338LysfsTer24) exhibited classical AOS features: scalp ACC, TTLD, microcephaly, and seizures (PMID:23522784; PMID:36059114; PMID:31368252). All variants segregate in the homozygous state consistent with autosomal-recessive inheritance.

The spectrum of EOGT pathogenic alleles comprises seven truncating or frameshift variants (e.g., c.78_81del (p.His27fs), c.1013dupA (p.Asn338LysfsTer24), c.1234C>T (p.Gln412Ter)), two canonical splice-site changes (c.621-2A>T, c.311+1G>T), and multiple missense substitutions (p.Arg377Trp, p.Trp207Ser) disrupting conserved residues (PMID:23522784; PMID:23860037; PMID:31368252).

Affected individuals uniformly present with scalp ACC (HP:0007385), variable TTLD, microcephaly (HP:0000252), and seizure disorder (HP:0001250) often with mild intellectual impairment and spastic paresis. The EOGT-associated recessive subtype may show fewer cardiovascular and ophthalmic anomalies compared to dominant forms.

Functional assays in HEK293T cells reveal that AOS-associated EOGT missense variants (p.Arg377Gln, p.Trp207Ser) and truncating alleles nearly abolish O-GlcNAcylation of Notch1 EGF repeats, with some mutants undergoing proteasomal degradation (PMID:25488668). Drosophila ortholog studies demonstrate essential roles in epithelial cell–matrix adhesion, supporting pathogenicity via loss of glycosyltransferase activity.

No conflicting reports have been described for EOGT in AOS, and multi-family segregation coupled with concordant functional data strongly supports causality. The mechanism of pathogenicity is loss of EGF-domain O-GlcNAcylation leading to disrupted Notch signaling and defective tissue morphogenesis.

Key take-home: Biallelic loss-of-function and missense variants in EOGT cause autosomal-recessive AOS with scalp ACC, limb defects, and neurological involvement; clinical testing of EOGT is recommended in AR AOS, and affected ACC sites require close surveillance for complications.

References

• American Journal of Human Genetics • 2013 • Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome PMID:23522784
• American Journal of Medical Genetics Part A • 2022 • Cutaneous squamous cell carcinoma in an autosomal-recessive Adams-Oliver syndrome patient with a novel frameshift pathogenic variant in the EOGT gene PMID:36059114
• American Journal of Medical Genetics Part A • 2019 • Adams-Oliver syndrome caused by mutations of the EOGT gene PMID:31368252
• European Journal of Human Genetics • 2014 • Autosomal recessive Adams-Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase PMID:23860037
• Journal of Biological Chemistry • 2015 • Impaired O-linked N-acetylglucosaminylation in the endoplasmic reticulum by mutated epidermal growth factor (EGF) domain-specific O-linked N-acetylglucosamine transferase found in Adams-Oliver syndrome PMID:25488668

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