A Novel MRTFB Missense Variant, c.479T>C p.(Leu160Pro), in a School-Aged Girl With Neurodevelopmental Disorder
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
MRTFB-related neurodevelopmental disorder is an autosomal dominant genetic condition marked by intellectual disability and neuropsychiatric symptoms with dysmorphic features. The MRTFB gene (also known as MKL2) encodes the protein myocardin-related transcription factor B, and it is required for skeletal myogenic differentiation. Few pathogenic variants in MRTFB have been published in the current literature. We present the case of a school-aged (between 5-12 years old) girl with a novel de novo MRTFB missense variant (c.479T>C p.(Leu160Pro)) along with our MRTFB gene disease association classification.
Case Presentation
The individual, a school-aged girl, exhibited intellectual disability, macrocephaly, attention-deficit/hyperactivity disorder (ADHD), staring episodes, dyslipidemia, and elevated liver enzymes. She has distinct physical features including macrocephaly, obesity with excessive hunger, tall stature, and craniofacial anomalies such as a flat facial profile, short philtrum, square teeth with diastema, sharply arched eyebrows, and downturned corners of the mouth. Additional findings included knuckle contractures, an inability to fully extend fingers and elbows, and a wide, inverted left foot. Dermatological conditions included post inflammatory hyperpigmentation, xerosis, and acanthosis nigricans. There is no reported family history of similar disease.
Diagnostic Workup
Her urine mucopolysaccharides (MPS) test was negative. Psychogenic nonepileptic seizure (PNES) was diagnosed based on electroencephalogram testing. Previous genetic testing, including chromosomal microarray, FMR1 repeat analysis (for Fragile X syndrome), and other multigene panel genetic testing (for obesity disorders, overgrowth syndromes and macrocephaly) yielded negative results. Whole exome genetic testing of this individual and both parents revealed a de novo missense MRTFB variant, NM_014048.4: c.479T>C p.(Leu160Pro). Maternity and paternity were confirmed based on the familial sequence data. This variant is absent in gnomAD v2, predicted damaging (score: 0.966) by the REVEL in silico prediction, and has not been previously published in the medical literature. It was initially classified as a variant of uncertain significance (VUS) with a limited gene-disease association between MRTFB and this disorder.
The gene-disease association was reevaluated one year later and was upgraded from limited to moderate association. This change was based on 2 new cases from a publication that was newly published in the interim along with our case evidence. Our gene-disease internal classification system is modeled after the ClinGen gene-disease validity framework. This new gene-disease association classification along with the identification as a de novo variant allowed for the variant's classification to be updated to likely pathogenic. This reclassification supports the role of the MRTFB variant in the individual’s neurodevelopmental phenotype and yielded a diagnostic finding for this individual.
Treatment and Management
This individual is taking medications including guanfacine and amphetamine/dextroamphetamine (Adderall) for ADHD, and levetiracetam for seizures. Semaglutide treatment for obesity was discontinued after adverse side effects. She is also receiving physical therapy and Floortime play therapy. Recommendations for her skin conditions were provided by her dermatologist. She was referred to orthopedics for her foot asymmetry and gait problems.
Outcome and Follow-Up
She continues to face challenges with obesity, hyperlipidemia, dyslipidemia, and elevated liver enzymes. She continues to take Adderall and started zonisamide for her PNES (staring episodes).
Discussion
In comparison with reported phenotypes from other MRTFB variants, c.310C>G p.(Arg104Gly) and c.271G>C p.(Ala91Pro), this individual showed overlapping features of intellectual disability, speech apraxia, developmental delays, and dysmorphic features, including widely spaced teeth.
Conclusion
This report describes a novel MRTFB variant linked to a complex neurodevelopmental disorder. The association between the gene and the individual’s phenotype, the variant's absence in a general population database, in silico predicted pathogenicity, and de novo occurrence underscores this variant’s pathogenicity. In addition, this case facilitated the identification of an association between MRTFB and autosomal dominant MRTFB-related neurodevelopmental disorder based on internal criteria. This case adds to the understanding of MRTFB-related disorders and highlights the importance of further studies to fully define the phenotypic spectrum and improve clinical management for affected individuals.
MRTFB-related neurodevelopmental disorder is an autosomal dominant genetic condition marked by intellectual disability and neuropsychiatric symptoms with dysmorphic features. The MRTFB gene (also known as MKL2) encodes the protein myocardin-related transcription factor B, and it is required for skeletal myogenic differentiation. Few pathogenic variants in MRTFB have been published in the current literature. We present the case of a school-aged (between 5-12 years old) girl with a novel de novo MRTFB missense variant (c.479T>C p.(Leu160Pro)) along with our MRTFB gene disease association classification.
Case Presentation
The individual, a school-aged girl, exhibited intellectual disability, macrocephaly, attention-deficit/hyperactivity disorder (ADHD), staring episodes, dyslipidemia, and elevated liver enzymes. She has distinct physical features including macrocephaly, obesity with excessive hunger, tall stature, and craniofacial anomalies such as a flat facial profile, short philtrum, square teeth with diastema, sharply arched eyebrows, and downturned corners of the mouth. Additional findings included knuckle contractures, an inability to fully extend fingers and elbows, and a wide, inverted left foot. Dermatological conditions included post inflammatory hyperpigmentation, xerosis, and acanthosis nigricans. There is no reported family history of similar disease.
Diagnostic Workup
Her urine mucopolysaccharides (MPS) test was negative. Psychogenic nonepileptic seizure (PNES) was diagnosed based on electroencephalogram testing. Previous genetic testing, including chromosomal microarray, FMR1 repeat analysis (for Fragile X syndrome), and other multigene panel genetic testing (for obesity disorders, overgrowth syndromes and macrocephaly) yielded negative results. Whole exome genetic testing of this individual and both parents revealed a de novo missense MRTFB variant, NM_014048.4: c.479T>C p.(Leu160Pro). Maternity and paternity were confirmed based on the familial sequence data. This variant is absent in gnomAD v2, predicted damaging (score: 0.966) by the REVEL in silico prediction, and has not been previously published in the medical literature. It was initially classified as a variant of uncertain significance (VUS) with a limited gene-disease association between MRTFB and this disorder.
The gene-disease association was reevaluated one year later and was upgraded from limited to moderate association. This change was based on 2 new cases from a publication that was newly published in the interim along with our case evidence. Our gene-disease internal classification system is modeled after the ClinGen gene-disease validity framework. This new gene-disease association classification along with the identification as a de novo variant allowed for the variant's classification to be updated to likely pathogenic. This reclassification supports the role of the MRTFB variant in the individual’s neurodevelopmental phenotype and yielded a diagnostic finding for this individual.
Treatment and Management
This individual is taking medications including guanfacine and amphetamine/dextroamphetamine (Adderall) for ADHD, and levetiracetam for seizures. Semaglutide treatment for obesity was discontinued after adverse side effects. She is also receiving physical therapy and Floortime play therapy. Recommendations for her skin conditions were provided by her dermatologist. She was referred to orthopedics for her foot asymmetry and gait problems.
Outcome and Follow-Up
She continues to face challenges with obesity, hyperlipidemia, dyslipidemia, and elevated liver enzymes. She continues to take Adderall and started zonisamide for her PNES (staring episodes).
Discussion
In comparison with reported phenotypes from other MRTFB variants, c.310C>G p.(Arg104Gly) and c.271G>C p.(Ala91Pro), this individual showed overlapping features of intellectual disability, speech apraxia, developmental delays, and dysmorphic features, including widely spaced teeth.
Conclusion
This report describes a novel MRTFB variant linked to a complex neurodevelopmental disorder. The association between the gene and the individual’s phenotype, the variant's absence in a general population database, in silico predicted pathogenicity, and de novo occurrence underscores this variant’s pathogenicity. In addition, this case facilitated the identification of an association between MRTFB and autosomal dominant MRTFB-related neurodevelopmental disorder based on internal criteria. This case adds to the understanding of MRTFB-related disorders and highlights the importance of further studies to fully define the phenotypic spectrum and improve clinical management for affected individuals.