First Report of an Inherited MYCBP2 Neurodevelopmental Disorder: Review of Proband and Parent Presentation
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
MYCBP2-associated neurodevelopmental disorder is a relatively newly described autosomal dominant genetic disorder. Significant characteristics included intellectual disability, developmental delay, epilepsy, facial dysmorphisms, ocular abnormalities, and autism spectrum disorder (ASD). Previously all known individuals have been described with de novo variants. Here we present the case of a proband with a maternally inherited MYCBP2-associated neurodevelopmental disorder. Neuropsychological assessment was obtained for both proband and mother who also had the same variant.
Case Presentation
The proband's past medical history is significant for prematurity at 34 weeks of gestation, global developmental delay, autism spectrum disorder, chronic constipation, and behavioral challenges around aggression, which included biting, scratching, and pinching. Language delay was first identified at his 15-month well child check.
Family history is remarkable for depression, anxiety, and dyslexia in the proband’s mother. Extended family history was significant for anxiety, depression, attention-deficit/ hyperactive disorder, developmental delays, and ASD.
Subspecialty care includes gastroenterology, developmental-behavioral pediatrics, and ophthalmology.
Diagnostic Workup
First-line genetic testing included negative chromosomal microarray and negative Fragile X testing. Whole exome sequencing was significant for a maternally inherited heterozygous pathogenic variant in MYCBP2, c.4409dup (p.Leu1470Phefs*7) resulting in a diagnosis ofMYCBP2-related neurodevelopmental disorder. The proband had an MRI brain with and without contrast which showed a normal corpus callosum. There was a cluster of non-specific punctate white matter lesions in the right centrum semiovale that were likely related to his history of prematurity. The proband had a normal eye exam performed under sedation.
Neuropsychological testing was limited in the proband due to the proband’s behavior and level of activity. Results of the evaluation suggested that overall developmental, reasoning, language, visual motor integration, and adaptive skills are below age-level expectations. Neuropsychological testing was also obtained for the proband's mother and showed a largely intact profile with mild executive inefficiencies. Overall, results for testing of the proband’s mother confirm that, despite having a pathogenic variant in MYCBP2, no significant cognitive impact is currently identifiable.
Treatment and Management
The proband received speech and occupational therapies in the outpatient setting from 2 years to 3.5 years of age. School services with an individualized education program (IEP) under the primary eligibility of autism began at age 3 years. He receives specially designed instruction in cognitive / pre-academic skills (30 minutes, 5 days per week), communication skills (30 minutes, 5 days per week), adaptive behavior (45 minutes, 5 days per week), and social / emotional skills (30 minutes, 5 days per week) as well as speech therapy services (30 minutes, 4 per month) all in the school setting. He is currently on the waitlist for Applied Behavior Analysis therapy in the outpatient setting. He was prescribed polyethylene glycol daily for his constipation starting at age 11 months. He was started on guanfacine for aggressive behavior at age 3 years.
Discussion
In the initial study describing MYCBP2-associated neurodevelopmental disorder, all individuals had de novo heterozygous pathogenic variants. We describe here the first case of an inherited MYCBP2-associated neurodevelopmental disorder in a pediatric patient inherited from a less-affected parent, expanding the phenotype of this neurodevelopmental disorder to include isolated mild executive dysfunction. Proband and parent both received evaluation with neuropsychology, also making this the first published neuropsychological profile in a 2-generation sample.
MYCBP2-associated neurodevelopmental disorder is a relatively newly described autosomal dominant genetic disorder. Significant characteristics included intellectual disability, developmental delay, epilepsy, facial dysmorphisms, ocular abnormalities, and autism spectrum disorder (ASD). Previously all known individuals have been described with de novo variants. Here we present the case of a proband with a maternally inherited MYCBP2-associated neurodevelopmental disorder. Neuropsychological assessment was obtained for both proband and mother who also had the same variant.
Case Presentation
The proband's past medical history is significant for prematurity at 34 weeks of gestation, global developmental delay, autism spectrum disorder, chronic constipation, and behavioral challenges around aggression, which included biting, scratching, and pinching. Language delay was first identified at his 15-month well child check.
Family history is remarkable for depression, anxiety, and dyslexia in the proband’s mother. Extended family history was significant for anxiety, depression, attention-deficit/ hyperactive disorder, developmental delays, and ASD.
Subspecialty care includes gastroenterology, developmental-behavioral pediatrics, and ophthalmology.
Diagnostic Workup
First-line genetic testing included negative chromosomal microarray and negative Fragile X testing. Whole exome sequencing was significant for a maternally inherited heterozygous pathogenic variant in MYCBP2, c.4409dup (p.Leu1470Phefs*7) resulting in a diagnosis ofMYCBP2-related neurodevelopmental disorder. The proband had an MRI brain with and without contrast which showed a normal corpus callosum. There was a cluster of non-specific punctate white matter lesions in the right centrum semiovale that were likely related to his history of prematurity. The proband had a normal eye exam performed under sedation.
Neuropsychological testing was limited in the proband due to the proband’s behavior and level of activity. Results of the evaluation suggested that overall developmental, reasoning, language, visual motor integration, and adaptive skills are below age-level expectations. Neuropsychological testing was also obtained for the proband's mother and showed a largely intact profile with mild executive inefficiencies. Overall, results for testing of the proband’s mother confirm that, despite having a pathogenic variant in MYCBP2, no significant cognitive impact is currently identifiable.
Treatment and Management
The proband received speech and occupational therapies in the outpatient setting from 2 years to 3.5 years of age. School services with an individualized education program (IEP) under the primary eligibility of autism began at age 3 years. He receives specially designed instruction in cognitive / pre-academic skills (30 minutes, 5 days per week), communication skills (30 minutes, 5 days per week), adaptive behavior (45 minutes, 5 days per week), and social / emotional skills (30 minutes, 5 days per week) as well as speech therapy services (30 minutes, 4 per month) all in the school setting. He is currently on the waitlist for Applied Behavior Analysis therapy in the outpatient setting. He was prescribed polyethylene glycol daily for his constipation starting at age 11 months. He was started on guanfacine for aggressive behavior at age 3 years.
Discussion
In the initial study describing MYCBP2-associated neurodevelopmental disorder, all individuals had de novo heterozygous pathogenic variants. We describe here the first case of an inherited MYCBP2-associated neurodevelopmental disorder in a pediatric patient inherited from a less-affected parent, expanding the phenotype of this neurodevelopmental disorder to include isolated mild executive dysfunction. Proband and parent both received evaluation with neuropsychology, also making this the first published neuropsychological profile in a 2-generation sample.