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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Molecular Basis of Adducted Thumbs Syndrome in the ...
Molecular Basis of Adducted Thumbs Syndrome in the Old Order Amish Community
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The molecular basis of Adducted Thumbs Syndrome (ATS) in the Old Order Amish (OOA) community has been identified as homozygosity for a pathogenic variant in the SMPD4 gene. Adducted thumbs syndrome is a rare disorder characterized by brain and respiratory tract malformations, microcephaly, adducted thumbs, hypotonia, and a poor prognosis. Two infants from the OOA community were evaluated and found to have clinical features of ATS, both of whom were homozygous for the SMPD4 variant while their parents were heterozygous.<br /><br />The Community Health Clinic (CHC) has also identified additional OOA individuals who are heterozygous for the SMPD4 variant and have had children clinically affected with ATS. It has been found that pathogenic variants in SMPD4 cause a neurodevelopmental disorder called neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA).<br /><br />Two case studies are discussed. Patient 2 had multiple malformations including adducted thumbs, cardiac defects, microcephaly, and seizures. They died at 6 months old. Patient 1 also had multiple malformations including cortical thumbs, cardiac anomalies, microcephaly, and seizures. They died at 10 months old. In both cases, genetic testing revealed the homozygous SMPD4 variant in the affected children.<br /><br />In addition to the case studies, the CHC has identified six other OOA families with children who had ATS and died at various ages. Testing revealed that all parents were heterozygous for the SMPD4 variant, indicating that the affected children were homozygous.<br /><br />The identified pathogenic variant in SMPD4 disrupts the consensus splice site in exon 5, which is predicted to cause disease. Experimental studies to confirm the pathogenicity of this variant and its effect on RNA splicing are needed. The findings suggest that NEDMABA and ATS are the same condition with overlapping features.<br /><br />Understanding the molecular basis of ATS allows for proactive carrier screening and confirmation of clinical diagnosis to direct appropriate treatment for affected infants, such as palliative care.
Asset Subtitle
Presenting Author - Nicole Bertsch, MS, CGC; Co-Author - Zineb Ammous, MD; Co-Author - Erik G. Puffenberger, PhD; Co-Author - Rhonda Anderson, MSN, FNP-C;
Meta Tag
Clinical History
Congenital Anomaly
Counseling
Delineation of Diseases
Dysmorphology
Genetic Testing
Genome sequencing
Genotype-Phenotype Correlations
Natural History
Phenotype
Phenotypic delineation of disorders
Pulmonary/respiratory malformations
Respiratory System
Co-Author
Zineb Ammous, MD
Co-Author
Erik G. Puffenberger, PhD
Co-Author
Rhonda Anderson, MSN, FNP-C
Presenting Author
Nicole Bertsch, MS, CGC
Keywords
Adducted Thumbs Syndrome
ATS
Old Order Amish
OOA
SMPD4 gene
neurodevelopmental disorder
microcephaly
arthrogryposis
structural brain anomalies
consensus splice site
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