Variants in NAA15 cause pediatric hypertrophic cardiomyopathy

Abstract

The NatA N‐acetyltransferase complex is important for cotranslational protein modification and regulation of multiple cellular processes. The NatA complex includes the core components of NAA10, the catalytic subunit, and NAA15, the auxiliary component. Both NAA10 and NAA15 have been associated with neurodevelopmental disorders with overlapping clinical features, including variable intellectual disability, dysmorphic facial features, and, less commonly, congenital anomalies such as cleft lip or palate. Cardiac arrhythmias, including long QT syndrome, ventricular tachycardia, and ventricular fibrillation were among the first reported cardiac manifestations in patients with NAA10‐related syndrome. Recently, three individuals with NAA10‐related syndrome have been reported to also have hypertrophic cardiomyopathy (HCM). The general and cardiac phenotypes of NAA15‐related syndrome are not as well described as NAA10‐related syndrome. Congenital heart disease, including ventricular septal defects, and arrhythmias, such as ectopic atrial tachycardia, have been reported in a small proportion of patients with NAA15‐related syndrome. Given the relationship between NAA10 and NAA15, we propose that HCM is also likely to occur in NAA15‐related disorder. We present two patients with pediatric HCM found to have NAA15‐related disorder via exome sequencing, providing the first evidence that variants in NAA15 can cause HCM.

Possible Catch-Up Developmental Trajectories for Children with Mild Developmental Delay Caused by NAA15 Pathogenic Variants

“…More interestingly, all affected individuals herein presented mild DD based on the scores of the CNBS-R2016 or ASQ. None of them had a complaint of congenital heart disease (i.e., cyanosis, palpitations, fatigue, and recurrent respiratory infections), and normal heart development was confirmed in one patient by the cardiac color ultrasound, which is different from previous reports [ 11 , 12 , 17 , 18 ]. In addition, catch-up developmental trajectories were noted in three affected children based on their improved neurodevelopmental scores and physical growth curve at different ages, especially for gross motor, personal–social, and language abilities.…”

“…NAA15 variants are in different domains, ranging from the second to the last exon. There is no obvious correlation between exonic localization and phenotype, and 81% of affected patients carry LGD variants [ 11 , 12 , 17 , 18 ].…”

“…To explore the DD severity and developmental trajectory of the patients with NAA15 pathogenic variant, we reviewed the detailed NDD phenotypes for 42 previous patients with NAA15 variant. We found that more than half of them (26/46 = 56.5%, Table 1 ) had mild to moderate ID/DD (including six patients with mild ID/DD, two patients with mild/moderate ID/DD, and 14 patients with moderate ID/DD) [ 11 , 12 , 17 , 18 ], and possible catch-up neurodevelopment was implied in three DD patients. Cheng et al reported a girl with a de novo variant in NAA15 (Individual 6, Cys484Arg) who was diagnosed as “global DD at the age of 32 months” and described as “improved neurodevelopment with age grow up” [ 17 ].…”

“…The pathogenicity of missense variants in NAA15 occurring via other mechanisms cannot be excluded because the missense constraint Z-score for NAA15 is 3.81, indicating its intolerance to missense variation [ 22 ]. Nine NAA15 missense variants have been reported (two are inherited, six are de novo, and one is unknown) [ 11 , 17 , 18 ], and the clinical features of NAA15 missense variants were similar to those of NAA15 LGD variants. Unstable protein expression caused by missense variants could result in degradative protein, similar to haploinsufficiency caused by the LOF variant.…”

Further Considerations in Childhood-Onset Hypertrophic Cardiomyopathy Genetic Testing

“…At least 30 genes can be responsible for HCM (6). Recent studies have used Whole Exome Sequencing to expand the HCM panel, resulting in possible new genes (7)(8)(9). Syndromic causes of HCM, such as VARS2 and FNIP1, are emerging genes for pediatric patients, identified by targeted clinical exome sequencing (10,11).…”