NAA10 variant in 38-week-gestation male patient: a case study

Abstract

We present a male patient born at 38-wk gestation with rhizomelic shortening of extremities, hepatomegaly, ventriculomegaly, heart failure, severely depressed left ventricular function, biventricular hypertrophy, and biatrial enlargement. Additional physical findings included anteriorly displaced anus, vertebral anomalies, and brachydactyly. The patient's cardiac malformations led to persistent hypotension, sinus tachycardia, and multiorgan failure in the absence of arrhythmias. Rapid whole-exome sequencing was ordered on day of life (DOL) 8. The patient's family elected to withdraw supportive care, and he passed away that evening. Whole-exome sequencing returned posthumously and identified a variant in NAA10, E100K. The genotype–phenotype was closest to Ogden syndrome or amino-terminal acetyltransferase deficiency. Typical features of this rare X-linked syndrome include progeroid appearance, failure to thrive, developmental delays, hypotonia, and cardiac arrhythmias. Other family members were tested and the patient's mother, who has a history of mild intellectual disability, as well as a daughter born later, were identified as carriers. All carriers showed no cardiac findings. The carrier sister has manifested developmental delay and cortical atrophy. Protein modeling, evolution, dynamics, population variant assessments, and immunoprecipitation depict the deleterious nature of the variant on the interactions of NAA10 with NAA15. These findings had subsequent implications for posthumous diagnosis of the index patient, for female carriers, and regarding family planning. We highlight how these rapid genetic tests and variant characterization can potentially lead to informed decision-making between health-care providers and family members of patients with critical or lethal conditions when treatment options are limited.

Case report: Rare among ultrarare—Clinical odyssey of a new patient with Ogden syndrome

“…All these patients may present with milder phenotype, such as non-syndromic intellectual disability ( McTiernan et al, 2018 ), up to significant malformations (septal defects, microcephaly) ( Ree et al, 2019 ; Afrin et al, 2020 ) and severe functional disorders—arrhythmias, developmental delays ( Casey et al, 2015 ; Ree et al, 2019 ). In siblings of some of the affected children, who were carriers of the mutation, was found a milder phenotype, consisting of individual malformations ( Afrin et al, 2020 ). Though in above cases the defects do not lead to early lethality, they leave a significant clinical mark on the quality of patients’ lives.…”

Expanding the Phenotypic spectrum ofNAA10-related neurodevelopmental syndrome andNAA15-related neurodevelopmental syndrome

“…Since the initial discovery of OS in 2011, multiple groups have reported additional variants either in NAA10 in both males and females (Bader et al 2020; Casey et al 2015; Cheng et al 2019; McTiernan et al 2021; Popp et al 2015; Ree et al 2019; Støve et al 2018; Afrin et al 2020; Esmailpour et al 2014; Johnston et al 2019; Gupta et al 2019; Saunier et al 2016; Maini et al 2021) or in the heterodimeric protein partner encoded by NAA15 (Cheng et al 2019; Cheng et al 2018; Ritter et al 2021; Ward et al 2021; Tian et al 2022). The collection of presenting symptoms for families with NAA10 variants is currently referred to as, “Ogden syndrome” or “ NAA10 -related syndrome”, and “ NAA15 -related syndrome” for families with NAA15 variants.…”

Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N-terminal acetylation

“…In the last decade, 21 NAA10 missense variants have been reported as pathogenic in 69 males and females and can be classified as causative of NAA10-related syndrome. The majority of these variants have been biochemically Casey et al 2015;Popp et al 2015;Saunier et al 2016;McTiernan et al 2018McTiernan et al , 2020McTiernan et al , 2021Støve et al 2018;Cheng et al 2019;Ree et al 2019;Bader et al 2020;Afrin et al 2020). Furthermore, a frameshift variant, a splice-site variant and three PAS variants in NAA10 have been associated with syndromic microphthalmia in 20 males (Cheng et al 2019;Esmailpour et al 2014;Johnston et al 2019).…”