A de novo heterozygous ACTC1 variant (NM_005159.5; c.650A>C, p.Lys217Thr) was found in Individual 2.
Case:Male, born at 39 weeks of gestation, evaluated during infancy-age 6.
DiseaseAssertion:Arthrogryposis multiplex congenita (AMC). The patient also had Shone's complex with coarctation of the aorta. Cardiomyopathy not reported.
Familyinfo:The patient was the first child of unrelated parents. No family history of arthrogryposis multiplex congenita was reported.
ParentalTesting:The ACTC1 c.650A>C (p.Lys217Thr) variant was identified as de novo. Neither parent was reported to carry the variant.
CasePresentingHPOs:HP:0002804, HP:0001762, HP:0001680, HP:0001188, HP:0000954, HP:0001845, HP:0001290, HP:0002194
CaseHPOFreeText:The patient was born at 39 weeks of gestation. At birth, he had limited range of motion in the wrists, fingers, thumbs, hips, and knees, along with bilateral clubfeet. Echocardiography revealed Shone's complex, including coarctation of the aorta, which required surgical repair. At age 1, he had clenched hands with deep single palmar creases, overlapping toes, and hypoplastic fifth toenails. He also had truncal hypotonia, mild lower extremity weakness, and delayed gross motor milestones. At age 3, moderate wrist contractures, thumb-in-palm deformities, and mild bilateral hip contractures were observed. He began walking independently at age 4. At age 5, he underwent additional heart surgery and pacemaker insertion.
CaseNotHPOs:Scoliosis: not identified on spine X-rays, cognitive difficulties: not reported
CaseNOTHPOFreeText:The patient did not have reported cognitive difficulties. Spine X-rays did not reveal scoliosis.
CasePreviousTesting:Genome sequencing was performed to identify genetic variants associated with the patient's clinical presentation. Echocardiography was used to identify Shone's complex and coarctation of the aorta.
GenotypingMethod:Genome sequencing. Plasmid sequences used for the functional experiments were verified by Sanger sequencing.
FunctionalAnalysis:In vitro functional studies were performed using MC3T3-E1 preosteoblastic cells. The p.Lys217Thr variant did not demonstrate a clear effect on ACTC1 protein expression or localization compared with wild-type ACTC1. The authors reported no apparent reduction in protein levels or impaired actin filament organization.
Variant:NM_005159.5 (ACTC1): c.650A>C; p.Lys217Thr.
ClinVar:not reported
CAID:not reported
gnomAD:not reported
AdditionalInfo:The variant was identified as de novo and classified as likely pathogenic using ACMG criteria (PS2, PM1, PM2, PP2, PP3). Although functional testing did not demonstrate a clear effect on ACTC1 protein expression or localization, the authors considered the variant likely pathogenic based on the genetic and clinical evidence.