ACTC1 variants result in a phenotype resembling Noonan syndrome
Clinical Genetics and Therapeutics
-
Primary Categories:
- Clinical Genetics
-
Secondary Categories:
- Clinical Genetics
Introduction
ACTC1, the gene that encodes alpha cardiac actin 1, is an established cause of various isolated cardiac abnormalities, including dilated and hypertrophic cardiomyopathy, atrial septal defects, and left ventricular non-compaction. Recent reports, however, suggest a potentially broader role for ACTC1 underlying not only multiple cardiac anomalies but also variable extracardiac malformations such as midline anomalies (diastema of the upper incisors, cleft lip, hypertelorism, kyphoscoliosis, and pectus excavatum), multiple congenital contractures, scoliosis, and overlapping phenotype with Noonan syndrome in at least one report. We report two individuals suspected of having Noonan syndrome in whom missense variants in ACTC1 were identified. We use the zebrafish model to demonstrate that these human variants cause developmental defects.
Case Presentation
Patient 1 is an 18-year-old female with a history of complex heart disease with a repaired double outlet right ventricle, coarctation of the aorta, and severe non-compaction of the left ventricle. She had a history of short stature (145cm at 18 years of age, Z= -2.83), primary amenorrhea, a duplicated collecting system of the right kidney, and mild left-sided sensorineural hearing loss. She had mild developmental delay and had a diagnosis of dyslexia. On physical exam, she was noted to have facial dysmorphism and neck webbing. Patient 2 is an 18-year-old female with a history of left ventricular non-compaction with normal function, ventricular septal defect, and mild transverse arch hypoplasia. She had a long history of short stature (142 cm at 18 years of age, Z= -3.2). On physical examination, she was noted to have down-slanted palpebral fissures, hypotelorism, ptosis, small ears, single palmar creases bilaterally, and pes planus.
Diagnostic Workup
For patient 1: exome sequencing identified a de novo previously unreported and initially classified as a variant of uncertain significance in ACTC1 (c.170 G>A, p.(G57D)) and maternally inherited likely pathogenic variant in TTN. For patient 2, exome sequencing identified a previously reported pathogenic variant that was not maternally inherited in ACTC1 (c.301G>A, p.(E101K)).
Treatment and Management
The available ACTC1 structure was used to analyze the effects of the variants on protein folding, stability, and function. To assess the effects of these ACTC1 variants, we used human ortholog to compare how wild-type ACTC1 and ACTC1 harboring p. G57D and p. E101K variants impact the cranial cartilage development of zebrafish larvae.
Outcome and Follow-Up
ACTC1 structure analysis for the reported variants revealed that all observed alterations in ACTC1 would negatively impact its stability and/or folding, altering ACTC1 function.
Using the zebrafish model, we found that at 4 days post fertilization, wild-type ACTC1 human mRNA injections had little impact on cranial development. In contrast, embryos injected with ACTC1 mRNA harboring ACTC1 variants G57D and E101K displayed markedly abnormal craniofacial skeletons. As in the clinical phenotype exhibited by ACTC1 patients, zebrafish embryos expressing ACTC1 variants G57D and E101K variants displayed an aberrant craniofacial patterning, as indicated by broadening of the angle of the ceratohyal cartilage, a major mandibular structure, reinforcing that they confer a loss of function effect and confirming the pathogenicity of the ACTC1 disease-associated variants
Discussion
ACTC1 is well established to underlie isolated cardiac abnormalities, including atrial septal defects, left ventricular noncompaction, and dilated and hypertrophic cardiomyopathy. Recently, missense variants in ACTC1 were found in individuals with multiple anomalies in what appeared to be an autosomal dominant disorder characterized by multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy. Here, we report individuals with missense variants in ACTC1 and phenotypes that include short stature, facial dysmorphism, and cardiovascular defects overlapping with RASopathy syndromes.
Conclusion
Pathogenic variants in ACTC1 are related to a phenotypic spectrum ranging from isolated cardiac abnormalities to complex heart defects with extracardiac manifestations that can overlap with Noonan syndrome. The zebrafish model allowed for the identification of craniofacial abnormalities, confirming the broad role of ACTC1 in morphogenesis. We suggest including ACTC1 when performing clinical testing for Noonan syndrome and related conditions.
ACTC1, the gene that encodes alpha cardiac actin 1, is an established cause of various isolated cardiac abnormalities, including dilated and hypertrophic cardiomyopathy, atrial septal defects, and left ventricular non-compaction. Recent reports, however, suggest a potentially broader role for ACTC1 underlying not only multiple cardiac anomalies but also variable extracardiac malformations such as midline anomalies (diastema of the upper incisors, cleft lip, hypertelorism, kyphoscoliosis, and pectus excavatum), multiple congenital contractures, scoliosis, and overlapping phenotype with Noonan syndrome in at least one report. We report two individuals suspected of having Noonan syndrome in whom missense variants in ACTC1 were identified. We use the zebrafish model to demonstrate that these human variants cause developmental defects.
Case Presentation
Patient 1 is an 18-year-old female with a history of complex heart disease with a repaired double outlet right ventricle, coarctation of the aorta, and severe non-compaction of the left ventricle. She had a history of short stature (145cm at 18 years of age, Z= -2.83), primary amenorrhea, a duplicated collecting system of the right kidney, and mild left-sided sensorineural hearing loss. She had mild developmental delay and had a diagnosis of dyslexia. On physical exam, she was noted to have facial dysmorphism and neck webbing. Patient 2 is an 18-year-old female with a history of left ventricular non-compaction with normal function, ventricular septal defect, and mild transverse arch hypoplasia. She had a long history of short stature (142 cm at 18 years of age, Z= -3.2). On physical examination, she was noted to have down-slanted palpebral fissures, hypotelorism, ptosis, small ears, single palmar creases bilaterally, and pes planus.
Diagnostic Workup
For patient 1: exome sequencing identified a de novo previously unreported and initially classified as a variant of uncertain significance in ACTC1 (c.170 G>A, p.(G57D)) and maternally inherited likely pathogenic variant in TTN. For patient 2, exome sequencing identified a previously reported pathogenic variant that was not maternally inherited in ACTC1 (c.301G>A, p.(E101K)).
Treatment and Management
The available ACTC1 structure was used to analyze the effects of the variants on protein folding, stability, and function. To assess the effects of these ACTC1 variants, we used human ortholog to compare how wild-type ACTC1 and ACTC1 harboring p. G57D and p. E101K variants impact the cranial cartilage development of zebrafish larvae.
Outcome and Follow-Up
ACTC1 structure analysis for the reported variants revealed that all observed alterations in ACTC1 would negatively impact its stability and/or folding, altering ACTC1 function.
Using the zebrafish model, we found that at 4 days post fertilization, wild-type ACTC1 human mRNA injections had little impact on cranial development. In contrast, embryos injected with ACTC1 mRNA harboring ACTC1 variants G57D and E101K displayed markedly abnormal craniofacial skeletons. As in the clinical phenotype exhibited by ACTC1 patients, zebrafish embryos expressing ACTC1 variants G57D and E101K variants displayed an aberrant craniofacial patterning, as indicated by broadening of the angle of the ceratohyal cartilage, a major mandibular structure, reinforcing that they confer a loss of function effect and confirming the pathogenicity of the ACTC1 disease-associated variants
Discussion
ACTC1 is well established to underlie isolated cardiac abnormalities, including atrial septal defects, left ventricular noncompaction, and dilated and hypertrophic cardiomyopathy. Recently, missense variants in ACTC1 were found in individuals with multiple anomalies in what appeared to be an autosomal dominant disorder characterized by multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy. Here, we report individuals with missense variants in ACTC1 and phenotypes that include short stature, facial dysmorphism, and cardiovascular defects overlapping with RASopathy syndromes.
Conclusion
Pathogenic variants in ACTC1 are related to a phenotypic spectrum ranging from isolated cardiac abnormalities to complex heart defects with extracardiac manifestations that can overlap with Noonan syndrome. The zebrafish model allowed for the identification of craniofacial abnormalities, confirming the broad role of ACTC1 in morphogenesis. We suggest including ACTC1 when performing clinical testing for Noonan syndrome and related conditions.