Incomplete Penetrance Associated With A Familial Loss of Function NAA15 Variant
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
The NAA15 gene encodes a component of the NatA N-acetyltransferase complex, which plays a role in the post-translational protein modification. Loss of function (LoF), truncating variants in NAA15 have been associated with intellectual disability. Other phenotypic features may also include, developmental delay, autism spectrum disorder, dysmorphic features, and congenital cardiac anomalies. An extensive literature review indicates that variants in the NAA15 gene are most often de novo, with only few reported cases with milder phenotype and inherited variant have been described in the literature to date. Here, we report a pediatric patient with a NAA15 pathogenic variant (c.1377del p.Glu460LysfsTer17 NM_057175.5) which was inherited from the father. The patient displays typical characteristics associated with the NAA15-related disorder, whereas his father remains completely asymptomatic.
Case Presentation
Our patient is an 8-year-old-male who presented to our Genetics clinic for evaluation of developmental delay and autism. The patient was born to a 28-year-old G2P2 mother at term via C-section due to failure to progress. Birth weight was 8 lbs & 9 oz, and length was 20 inches. Apgar scores were low, and infant required intubation for 2 days due to pulmonary hypertension.
Family history was non-contributory, and both parents are of Indian (Hyderabad) ancestry, with consanguinity denied. Developmental delays were notable at 2 months of age, when the patient exhibited feeding and swallowing difficulties that necessitating gastroenterology evaluation.
The patient began crawling at 9 months and started walking at 17 months of age. At 18 months, significant motor and speech regression were observed, along with suspected seizure activity. An autism diagnosis was confirmed at this age. Upon examination, patient was nonverbal and demonstrated poor eye contact. Patient’s growth parameters were within normal limit for his age and Hirsutism was noted. Dysmorphic features included ached, dark eyebrows, large palpebral fissures, and low seat ears. The oropharyngeal examination revealed long upper central incisors and malformed teeth, and normal palate. Musculoskeletal examination indicated normal joint movement, alongside persistent fetal finger pads and pes planus..
Diagnostic Workup
The chromosome microarray came normal. Swallow study was normal. Whole exome sequencing revealed heterozygous pathogenic variant in the NAA15 gene (c.1377del p.Glu460LysfsTer17 NM_057175.5) inherited from the father and a hemizygous variant of uncertain significance in the OPHN1 gene (c.770C>A p.Pro257His NM_ 0025473 )inherited from the mother. MRI brain was normal.Metabolic work up came normal .
Treatment and Management
Our patient receives speech therapy , OT and ABA therapy. Provided with Structured Special needs class room. Patient was receiving high dose Probiotics, digestive enzymes and Buspirone.
Outcome and Follow-Up
Our patient remains non- verbal with developmental and educational support, and communicates parents by grabbing their hands and taking them to the object he needs.Patient continues follow up with Neurology and Genetics.Ophthalmology evaluation and audiology testing recommended
Discussion
The patient's father, a 39-year-old male, exhibits no evidence of physical or cognitive phenotypic abnormalities associated with the NAA15 loss-of-function variant identified in his child.
Our case adds to the body of evidence regarding the familial inheritance of the NAA15 variants from an unaffected parent, further illustrating the variant's variable expressivity and incomplete penetrance associated with NAA15-associated disease.
Conclusion
The inheritance pattern of the NAA15 variants is primarily de novo; however, there have been a limited number of cases that exhibit familial inheritance of the LoF variants. Notably, one study documented three families where a mildly affected parent had affected siblings, while another identified four de novo variants alongside two that were inherited from either unaffected or mildly affected parents, suggesting variable expressivity. The estimated penetrance of the LoF NAA15 variants is 35.3%. Our case adds to the body of evidence regarding the familial inheritance of the NAA15 variants from an unaffected parent, further illustrating the variant's variable expressivity and incomplete penetrance associated with NAA15-associated disease.
Future identification of additional affected individuals will be necessary to further refine the clinical phenotype and to understand the underlying mechanisms by which reduced expression or altered function of NAA15 contributes to these phenotypes.
The NAA15 gene encodes a component of the NatA N-acetyltransferase complex, which plays a role in the post-translational protein modification. Loss of function (LoF), truncating variants in NAA15 have been associated with intellectual disability. Other phenotypic features may also include, developmental delay, autism spectrum disorder, dysmorphic features, and congenital cardiac anomalies. An extensive literature review indicates that variants in the NAA15 gene are most often de novo, with only few reported cases with milder phenotype and inherited variant have been described in the literature to date. Here, we report a pediatric patient with a NAA15 pathogenic variant (c.1377del p.Glu460LysfsTer17 NM_057175.5) which was inherited from the father. The patient displays typical characteristics associated with the NAA15-related disorder, whereas his father remains completely asymptomatic.
Case Presentation
Our patient is an 8-year-old-male who presented to our Genetics clinic for evaluation of developmental delay and autism. The patient was born to a 28-year-old G2P2 mother at term via C-section due to failure to progress. Birth weight was 8 lbs & 9 oz, and length was 20 inches. Apgar scores were low, and infant required intubation for 2 days due to pulmonary hypertension.
Family history was non-contributory, and both parents are of Indian (Hyderabad) ancestry, with consanguinity denied. Developmental delays were notable at 2 months of age, when the patient exhibited feeding and swallowing difficulties that necessitating gastroenterology evaluation.
The patient began crawling at 9 months and started walking at 17 months of age. At 18 months, significant motor and speech regression were observed, along with suspected seizure activity. An autism diagnosis was confirmed at this age. Upon examination, patient was nonverbal and demonstrated poor eye contact. Patient’s growth parameters were within normal limit for his age and Hirsutism was noted. Dysmorphic features included ached, dark eyebrows, large palpebral fissures, and low seat ears. The oropharyngeal examination revealed long upper central incisors and malformed teeth, and normal palate. Musculoskeletal examination indicated normal joint movement, alongside persistent fetal finger pads and pes planus..
Diagnostic Workup
The chromosome microarray came normal. Swallow study was normal. Whole exome sequencing revealed heterozygous pathogenic variant in the NAA15 gene (c.1377del p.Glu460LysfsTer17 NM_057175.5) inherited from the father and a hemizygous variant of uncertain significance in the OPHN1 gene (c.770C>A p.Pro257His NM_ 0025473 )inherited from the mother. MRI brain was normal.Metabolic work up came normal .
Treatment and Management
Our patient receives speech therapy , OT and ABA therapy. Provided with Structured Special needs class room. Patient was receiving high dose Probiotics, digestive enzymes and Buspirone.
Outcome and Follow-Up
Our patient remains non- verbal with developmental and educational support, and communicates parents by grabbing their hands and taking them to the object he needs.Patient continues follow up with Neurology and Genetics.Ophthalmology evaluation and audiology testing recommended
Discussion
The patient's father, a 39-year-old male, exhibits no evidence of physical or cognitive phenotypic abnormalities associated with the NAA15 loss-of-function variant identified in his child.
Our case adds to the body of evidence regarding the familial inheritance of the NAA15 variants from an unaffected parent, further illustrating the variant's variable expressivity and incomplete penetrance associated with NAA15-associated disease.
Conclusion
The inheritance pattern of the NAA15 variants is primarily de novo; however, there have been a limited number of cases that exhibit familial inheritance of the LoF variants. Notably, one study documented three families where a mildly affected parent had affected siblings, while another identified four de novo variants alongside two that were inherited from either unaffected or mildly affected parents, suggesting variable expressivity. The estimated penetrance of the LoF NAA15 variants is 35.3%. Our case adds to the body of evidence regarding the familial inheritance of the NAA15 variants from an unaffected parent, further illustrating the variant's variable expressivity and incomplete penetrance associated with NAA15-associated disease.
Future identification of additional affected individuals will be necessary to further refine the clinical phenotype and to understand the underlying mechanisms by which reduced expression or altered function of NAA15 contributes to these phenotypes.
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