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Published in final edited form as: Am J Med Genet A. 2020 Oct 26;185(1):228–233. doi: 10.1002/ajmg.a.61928

Variants in NAA15 cause pediatric hypertrophic cardiomyopathy

Alyssa Ritter 1,2, Justin H Berger 2, Matthew Deardorff 3, Kosuke Izumi 1,4, Kimberly Y Lin 2, Livija Medne 1, Rebecca C Ahrens-Nicklas 1,4
PMCID: PMC8007079  NIHMSID: NIHMS1678996  PMID: 33103328

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.

Keywords: exome sequencing, hypertrophic cardiomyopathy, NAA10, NAA15, neurodevelopmental disorder

1 |. INTRODUCTION

The N-acetyltransferase (NatA) complex regulates multiple cellular functions, including cell survival and cell cycle control, through cotranslational protein modification (Arnesen et al., 2006; Deng et al., 2019; Dörfel & Lyon, 2015; Lee et al., 2018; Linster et al., 2015; Lyon, 2019; Mullen et al., 1989; Myklebust et al., 2015). The NatA complex is a trimer or tetramer composed of: NAA15-NAA10-HYPK, NAA15-NAA10-NAA50, or NAA15-NAA10-HYPK-NAA50; NAA10 and NAA15 are the core components for the NatA activity (Arnesen et al., 2010; Deng et al., 2020). NAA10 is the catalytic subunit while NAA15 is an obligatory auxiliary subunit providing ancohoring to the ribosome and proper substrate specificity of NAA10 (Arnesen et al., 2005; Deng et al., 2019; Dörfel & Lyon, 2015; Gautschi et al., 2003; Lee et al., 2018; Liszczak et al., 2013; Lyon, 2019; Mullen et al., 1989; Myklebust et al., 2015; Van Damme et al., 2011). Both NAA10 and NAA15 have been associated with neurodevelopmental syndromes with overlapping clinical features, including variable intellectual disability, dysmorphic facial features, and, less commonly, congenital anomalies such as cleft lip or palate (Cheng et al., 2018, 2020).

NAA10 has been associated with a variant of phenotypes including an X-linked disorder with developmental delay, dysmorphic features and lethal cardiac arrhythmias, Lenz microphthalmia syndrome, Ogden syndrome, and neurodevelopmental disorders (Casey et al., 2015; Esmailpour et al., 2014; Johnston et al., 2019; Myklebust et al., 2015; Popp et al., 2015; Ree et al., 2019; Rope et al., 2011; Sauiner et al., 2016; Sidhu et al., 2017). The largest report of patients with NAA10-reated syndrome, as published by Cheng et al. in 2020, included 23 individuals from 23 families. Characteristic features included developmental delay, intellectual disability (ID), autism spectrum disorder, muscular hypotonia, dysmorphic facial features, and less commonly cardiac disease, including hypertrophic cardiomyopathy in a small number of patients (Cheng et al., 2020; Støve et al., 2018).

NAA15 was implicated in human disease after several studies identified de novo, loss-of-function NAA15 variants in large cohorts of patients with autism spectrum disorder and/or ID (Stessman et al., 2017; Zhao et al., 2018). In a large cohort of 38 patients with NAA15 variants from 33 families, common features included variable developmental delay, autism spectrum disorder or behavior abnormalities, muscular hypotonia, congenital cardiac defects, and skeletal or connective tissue abnormalities (Cheng et al., 2018, 2020). Notably, NAA10- and NAA15-related disorders have much phenotypic overlap, including variable ID, motor impairment, behavior abnormalities, and skeletal anomalies. Patients with missense variants have also been reported. These variants have been shown to affect either stability or activity of the NatA complex (Cheng et al., 2018). However, the clinical spectrum of NAA15-related syndrome is less well-delineated than that of NAA10-related syndrome and less is known about the cardiac phenotype. Herein, we present the first two patients with NAA15-related disorder who presented with pediatric HCM, providing evidence that variants in NAA15 are associated with pediatric HCM.

2 |. METHODS

Clinical trio exome sequencing for Patient 1 was performed at the Division of GenomicDiagnostics at Children’s Hospital of Philadelphia via methods previously described (Gibson et al., 2018). Clinical trio exome sequencing for Patient 2 was performed at GeneDx. Informed consent for publication of this information was obtainedfrom both families. Literature review using terms “NAA10”and “NAA15” was performed and three articles describingclinical information or clinical reports of patients with NAA15-related disorder were identified.

3 |. RESULTS

Three publications were identified which reported clinical information for 38 individuals with NAA15-related disorder. Phenotypic findings are summarized in Table 1. The most commonly reported features include: intellectual disability, speech and motor delays, behavior issues, and mild dysmorphic features.

TABLE 1.

Summary of clinical features of NAA15-related disorder

 Patient #1  Patient #2
 NAA15 variant c.1009_1012delGAAA c.79A > G
 Transcript NM_057175.4 NM_057175.3
 AA change p.Glu337fs p.Arg27Gly
 Inheritance de novo de novo
 Classification Pathogenic Likely pathogenic
 Publication Not previously published Not previously published Cheng et al. 2018 Cheng et al. 2020 Total Percent
 Brain structure/function
 Intellectual disability Too young Mild 23/23 4/6 28/30 93.3
 ASD/ADHD/behavior
issues		 Too young + 30/33 4/6 35/40 87.5
 Abnormal brain MRI Not done Not done 2/11 1/3 3/14 21.4
 Speech delay + + 32/33 3/5 37/40 92.5
 Seizures − − 6/26 4/5 10/33 30.3
 Motor impairment
 Motor delay + + 31/32 3/5 36/39 92.3
 Muscular Hypotonia + + 7/18 0/4 9/24 37.5
 Feeding difficulties + − 8/14 0/3 9/19 47.4
 Cardiovascular
 Congenital cardiac defects − − 4/19 1/4 5/23 21.7
 Major vessel anomalies − − 2/19 Unk 2/19 10.5
 Arrhythmias − − 1/19 Unk 1/19 5.3
 Hypertension − − 1/19 Unk 1/19 5.3
 HCM + + 0/19 0/6 2/27 7.4
 Other
 Mild dysmorphic features + + 18/28 4/5 24/35 68.6
 Skeletal or connective tissue defects + + 8/20 1/4 11/26 42.3
 Ophthalmologic +, entropion with corneal irritation; hyperopia +, amblyopia 2/28 3/6 7/36 19.4
 ENT Bilateral hearing loss Mild to moderate conductive hearing loss; chronic OM 0/32 0/6 2/40 5.0
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Abbreviations: +, positive/present; −, negative/absent; AA, amino acid; ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; ENT, otolaryngology; HCM, hypertrophic cardiomyopathy; MRI, magnetic resonance imaging; OM, otitis media; unk, unknown.

4 |. CASE REPORTS

4.1 |. Patient 1

Patient 1 initially presented to medical attention at 2 months of age with tachypnea and tachycardia. He was the product of a naturally conceived, uncomplicated pregnancy to a 38 year-old G4P3-P4 mother. He was born at 37 weeks gestation weighing 2.55 kg (z = −1.78) and measuring 47.5 cm (z = −2.21) in length. He had no major complications in the neonatal period. Echocardiographic evaluation (Figure 1) demonstrated HCM, with features including hyperdynamic left ventricle (LV) systolic function, quasi-obliteration of the LV cavity in systole, asymmetric septal hypertrophy (9 mm, Z-score + 8) and mild to moderate obstructive HCM with peak gradient of 52 mmHg (mean 22 mmHg). There was mild mitral regurgitation and mild diastolic dysfunction (by mitral inflow E/e’, an echocardiographic measure of diastolic dysfunction focusing on mitral inflow to estimate LV compliance). His electrocardiogram (ECG) showed sinus rhythm with a normal QTc and met voltage criteria for LV hypertrophy. A comprehensive evaluation for inborn errors of metabolism and storage diseases was unremarkable. No family history of cardiomyopathy, arrhythmias, or neurodevelopmental disorders was reported. Chromosomal SNP microarray was normal. Expedited trio exome sequencing was recommended due to his new diagnosis of infantile cardiomyopathy. Clinical trio exome sequencing with confirmed parentality identified a de novo, pathogenic variant in NAA15 [NM_057175.3]: c.1009_1012delGAAA, p.Glu337Arg*5. No other reportable or clinically significant variants were identified.

FIGURE 1.

FIGURE 1

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Representative cardiac testing from NAA15 patients. Echocardiographic images from Patient 1 (a-b) at diagnosis at 2 months and Patient 2 (c-d) at age 7 years. (a) Apical five-chamber image demonstrating asymmetrical septal hypertrophy measuring 9 mm in end-diastole (z score + 8). In supplemental video, there is hyperdynamic LV systolic function with near-complete cavitary obliteration in systole. With color Doppler (not shown), there is mild mitral regurgitation, no aortic insufficiency and flow acceleration beginning in the mid-LV cavity (peak 52/mean 22 mmHg). There is mild diastolic dysfunction by mitral inflow E/e’ (echocardiographic measure of diastolic dysfunction focusing on mitral inflow to estimate LV compliance, data not shown). (b) Parasternal long axis image in end-diastole re-demonstrating moderate asymmetric septal hypertrophy. (c) Apical five-chamber demonstrating a focal area of septal hypertrophy measuring 10 mm (z score + 5). In supplemental videos, there is normal LV systolic shortening. With color Doppler, there is no mitral or aortic regurgitation, and minimal flow acceleration beginning at the area of septal hypertrophy (peak 11/mean 6 mmHg). (d) Parasternal long axis images in end-diastole with septal hypertrophy. There is systolic anterior motion of the mitral valve in the supplemental video. (e) Parasternal short axis demonstrates otherwise-normal appearing LV cavity. (f) EKG from Patient 1 is normal sinus rhythm with left ventricular hypertrophy and reciprocal ST segment changes. (h), EKG from Patient 2 with normal sinus rhythm and mid-precordial q waves suggestive of septal hypertrophy [Color figure can be viewed at wileyonlinelibrary.com]

Patient 1 is now 17 months old with a history of severe infantile eczema, chronic constipation, lower eyelid entropion, and muscular hypotonia (Table 1). His cardiac function and degree of hypertrophy have remained stable on propanolol monotherapy. He has global developmental delays, first achieving sitting at 9 months and walking at 17 months. He has significant expressive speech delay. Growth paramters at last evaluation were notable for height at 77.5 cm (z = −1.45), weight at 10.4 kg (z = −0.30), and head circumference at 47.5 cm (z = 0.22). Physical examination was notable for epicanthal folds, cupped and prominent ears, muscular hypotonia, and dry skin with erythema and excoriation.

4.2 |. Patient 2

Patient 2 is an 8-year-old male who presented at 6-years-old to cardiology for evaluation of a heart murmur identified at a routine pediatrics visit. Echocardiogram was notable for normal LV systolic function, trivial LV outflow obstruction (peak 11 mmHg, mean 6 mmHg) secondary to a localized septal thickening (10 mm, Z-score + 5) and systolic anterior motion of the mitral valve (Figure 1). His ECG showed normal QTc and lateral q waves, suggestive of septal hypertrophy. Subsequent evaluations noted persistent focal septal hypertrophy (maximally 14 mm, Z-score + 10), consistent with a diagnosis of mild-moderate HCM without obstruction. He does not currently require any cardiac medications.

He was the product of an uncomplicated pregnancy to a 31-year-old G1P0-P1 mother. He was born at 38 weeks 6 days gestation weighing 2.77 8 kg (z = −1.28) and measuring 46.4 cm (z = −1.36) in length. He had no major complications in the neonatal period. His medical history is notable for muscular hypotonia, amblyopia, recurrent otitis media, unilateral mild-to-moderate conductive hearing loss, and lateral penile chordee (Table 1). He had global developmental delays, with sitting at 7 months, walking at 19 months, and first word at 18 months. Neuropsychological testing was notable for full scale intellectual quotient (FSIQ) of 94. He is currently receiving special education services for specific learning disabilities, including attention difficulties, deficits in working memory, and fine motor delay. No family history of cardiomyopathy, arrhythmia, neurodevelopmental disorders, or congenital anomalies was reported. Physical examination at 7 years old was notable for epicanthal folds, upslanting palpebral fissures, prominent forehead, depressed nasal bridge with broad nasal tip, and bilateral fifth finger clinodactyly of both fingers and toes. Growth was notable for height at 122.7 cm (z = −1.29), weight at 24.6 kg (z = −0.56), and head circumference at 50.5 cm (z = −1.42).

A multi-gene cardiomyopathy panel identified a variant of uncertain significance (VUS) in FLNC (NM_001458.5, c. 8019C>G, p. His2673Gln) and a single intronic VUS in GAA (NM_000152.5, c. 858 + 4C>G). Chromosomal microarray was normal. Clinical trio exome sequencing with confirmed parentality identified a de novo, likely pathogenic variant in NAA15 [NM_057175.3]: c.79A>G, p.R27G. No additional reportable or clinically relevant variants were identified.

4.3 |. Variant interpretation

The de novo variant identified in Patient 1, NAA15 c.1009_1012delGAAA, results in a frameshift in the transcript followed by a premature stop codon five amino acids downstream. The variant has been previously reported in two unrelated individuals with NAA15-related syndrome who have heterotaxy, congenital heart disease, developmental delay, and muscular hypotonia (Cheng et al., 2018; Zaidi et al., 2013). Functional analysis has shown almost complete absence of mutant NAA15 mRNA, supporting that this variant results in nonsense-medicated delay resulting in loss of function allele (Cheng et al., 2018). This variant meets criteria to be classified as pathogenic using American College of Medical Genetics criteria PVS1 and PS2 (Richards et al., 2015).

The variant identified in Patient 2, NAA15 c.79A>G, is a de novo missense variant in exon 2 of 20. It is not present in large population cohorts (Karczewski et al., 2020). In silico analyses support a deleterious effect (Choi & Chan, 2015; Ng & Henikoff, 2003; Schwartz et al., 2014). Missense variants occur significantly less often than expected per investigation of population databses (Karczewski et al., 2020). Other missense variants have been reported in NAA15 with variable features ranging from isolated neurodevelopmental disability to congenital heart disease (Cheng et al., 2020). This variant meets criteria to be classified as likely pathogenic using ACMG criteria PS2-moderate, PM2, PP2, and PP3 (Richards et al., 2015).

5 |. DISCUSSION

Both patients reported here presented for genetics evaluation due to hypertrophic cardiomyopathy and were subsequently identified to have likely pathogenic or pathogenic de novo variants in NAA15. They also other common features of the disorder, including muscular hypotonia, developmental delays, mild dysmorphic features, and ophthalmologic findings. Similar to several patients with missense variants in NAA15, Patient 2 has a history of mild developmental delay and specific learning disabilities, but relatively preserved intellectual functioning on neuropsychological testing (Cheng et al., 2018). A review of previously reported patients with NAA15-related disorder, as summarized in Table 1, noted one patient with a history of cardiac arrhythmias and no other patients with HCM (Cheng et al., 2018, 2020). Other rare findings in our patients include lower eyelid ectropion, refractive errors, and conductive hearing loss. Reassuringly, both patients have had relatively stable cardiac function since diagnosis; however, it is too early to predict the clinical course of NAA15-related HCM.

Given the functional relationship between NAA10 and NAA15 and previous reports of HCM due to NAA10 variants, it is logical that pathologic variants in NAA15 could also lead to HCM. It is possible that NAA10 and NAA15 are more frequently responsible for genetic predisposition to HCM than was previously recognized, due in part to the variability of manifestations and to relatively mild intellectual impairments, which may not prompt a clinical genetics evaluation.

Further identification of patients with NAA15-related syndrome is needed in order to fully delineate the phenotypic spectrum of this diagnosis, including the proportion of patients with HCM. Early identification of HCM is key for management and treatment of the disease. Given the variable age of onset seen in our two patients, and the variable age of onset of HCM as a whole, it is critically important that clinicians are aware of the risk for HCM in NAA15-related syndrome and provide appropriate cardiac surveillance over the lifespan. In conclusion, NAA15-related syndrome should be considered as a differential diagnosis for any pediatric patient presenting with HCM and developmental delay.

ACKNOWLEDGMENTS

The authors greatly appreciate the families for permission to publish this article. Dr. Berger receives support from the National Institutes of Health/National Heart Lung and Blood Institute (T32 HL1007915). Dr. Ahrens-Nicklas receives support from the National Institutes of Health (NINDS, K08NS105865).

Funding information

National Heart, Lung, and Blood Institute, Grant/Award Numbers: T32, HL1007915; National Institute of Neurological Disorders and Stroke, Grant/Award Number: K08NS105865

Footnotes

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT

Research data are not shared due to privacy or ethical restrictions.

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