NAA10 – Ogden syndrome

Ogden syndrome is a rare X-linked recessive neurodevelopmental disorder caused by pathogenic variants in the NAA10 gene, which encodes the catalytic subunit of the NatA N-terminal acetyltransferase complex. Affected individuals typically present in infancy with hypotonia, global developmental delay, dysmorphic facial features, failure to thrive, and fatal cardiac arrhythmias. To date, over 20 unrelated children have been reported worldwide, including both hemizygous males and heterozygous females with de novo or familial variants ([PMID:28967461]). The consistent phenotype across diverse ethnic backgrounds supports a common molecular etiology.

Inheritance is X-linked recessive, with most male probands exhibiting severe, often lethal, disease in infancy and heterozygous females showing variable expressivity. A de novo c.247C>T (p.Arg83Cys) variant was identified in a 14-year-old girl with evolving neurological features including epileptic encephalopathy and extrapyramidal signs ([PMID:28967461]). Rapid whole-exome sequencing in a male neonate revealed a c.298G>A (p.Glu100Lys) change associated with multiorgan failure and early death, confirming pathogenicity in hemizygous males ([PMID:33335012]). X-inactivation studies in females demonstrate mosaic expression that may modify disease severity.

Recurrence of a founder missense variant, c.109T>C (p.Ser37Pro), in two independent families resulting in eight affected males provides strong segregation evidence for X-linked recessive inheritance and disease causation ([PMID:34075687]). Carrier mothers and female siblings are typically asymptomatic or have mild developmental delay, consistent with skewed X-inactivation in blood. No unaffected hemizygous males have been reported, underscoring complete penetrance in males.

The NAA10 variant spectrum in Ogden syndrome is dominated by missense changes within the acetyltransferase domain. Beyond p.Ser37Pro, recurrent de novo variants include p.Arg83Cys, p.Val111Gly, and p.Glu100Lys, all shown to impair enzyme stability or catalytic activity. Splice-site and polyadenylation signal mutations further expand the allelic series. A single representative variant, c.247C>T (p.Arg83Cys), has been confirmed as pathogenic in multiple unrelated probands and functional assays ([PMID:28967461]).

Experimental evidence supports a loss-of-function mechanism via impaired N-terminal acetylation. Yeast models expressing S37P Naa10p exhibit reduced cellular fitness, dysregulated chaperone expression, and pseudo-diploid gene expression, mirroring human disease features ([PMID:27668839]). In vitro acetylation assays demonstrate markedly reduced enzymatic activity for p.Ser37Pro and p.Arg83Cys mutants, and iPSC-derived cardiomyocytes with NAA10-R4S mutations show repolarization defects consistent with clinical arrhythmias ([PMID:21700266]).

Taken together, the genetic and functional data establish a definitive association between NAA10 variants and Ogden syndrome. Clinically, molecular diagnosis enables early cardiac monitoring, neurological evaluation, and genetic counseling. Key take-home: Pathogenic NAA10 missense variants cause X-linked Ogden syndrome through loss of N-terminal acetyltransferase activity, guiding diagnostic and management strategies in affected families.

References

• Pediatric neurology • 2017 • Clinical Manifestations Associated With the N-Terminal-Acetyltransferase NAA10 Gene Mutation in a Girl: Ogden Syndrome. PMID:28967461
• American journal of medical genetics. Part A • 2021 • Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature. PMID:34075687
• American journal of human genetics • 2011 • Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. PMID:21700266
• Yeast (Chichester, England) • 2017 • Proteomic and genomic characterization of a yeast model for Ogden syndrome. PMID:27668839

Evidence Based Scoring (AI generated)