Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome

Abstract

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation in NAA10 and NAA15 in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals with NAA10 variants and 19 individuals with NAA15 variants, which were added to all known cases (N = 106 for NAA10 and N = 66 for NAA15). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands with NAA10 variants is significantly lower than the probands with NAA15 variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with an NAA15 frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end of NAA10 have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.

Ophthalmic Manifestations of NAA10-Related and NAA15-Related Neurodevelopmental Syndrome: Analysis of Cortical Visual Impairment and Refractive Errors

“…Table 5 compares the prevalence of CVI, myopia, astigmatism, strabismus, nystagmus, and hyperopia in our cohort to 106 previously reported cases, for a total of 173 individuals including those reported in this paper. Our cohort had significant overlap with the cohort reported previously 7 . However, the 37 probands from this paper who were not in our cohort were analyzed separately as seen in Table 5 .…”

“…Previous literature suggests that NAA10 individuals present with more severe phenotypes than NAA15 individuals 7 . In terms of the ophthalmic phenotypes, we found no significant differences between NAA10 and NAA15 presentations.…”

“…Interestingly, in comparing presentations across demographics, we found that NAA10 males were significantly less likely to have astigmatism compared to NAA10 females (p<0.05) ( Supplementary Figure S1e ). This significance is likely due to a small sample size of males, as mutations in NAA10 are more lethal in males 7 . Perhaps NAA10 males who would have had ophthalmologic manifestations died due to more serious systemic dysfunction.…”

Computational facial analysis for rare Mendelian disorders

“…Besides, the authors further perform the same analysis based on the different variant types in PHIP cohort to investigate whether we can distinguish patients based on the mutation types (Figure 6). Moreover, Lyon et al utilized GestaltMatcher to show that the patients with NAA10 ‐related neurodevelopmental syndrome and NAA15 ‐related neurodevelopmental syndrome shared a similar facial phenotype (Lyon et al, 2023). The tSNE plot in Figure 7 showed that the patients with NAA10 and NAA15 are similar and did not distribute in two clusters.…”

“…It means that NAA10 and NAA15 patients presented a similar facial phenotype based on the GestaltMatcher analysis. This figure was published in the original paper (Lyon et al, 2023) as supplementary figs. 7 and 8.…”