Clinical and Molecular Characterization of a Novel Homozygous Frameshift Variant in AEBP1-Related Classical-like Ehlers Danlos Syndrome Type 2 with Comparison to Previously Reported Rare Cases

Zong Yi Ha; Chieko Chijiwa; Suzanne Lewis

doi:10.3390/genes15040461

Clinical and Molecular Characterization of a Novel Homozygous Frameshift Variant in AEBP1-Related Classical-like Ehlers Danlos Syndrome Type 2 with Comparison to Previously Reported Rare Cases

Genes (Basel). 2024 Apr 6;15(4):461. doi: 10.3390/genes15040461.

Authors

Zong Yi Ha¹, Chieko Chijiwa^{1

2}, Suzanne Lewis^{1

2

3}

Affiliations

¹ Department of Medical Genetics, University of British Columbia, C234-4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
² The BC Provincial Medical Genetics Program, University of British Columbia, C234-4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
³ BC Children's Hospital Research Institute, University of British Columbia, C234-4500 Oak Street, Vancouver, BC V6H 3N1, Canada.

Abstract

Recently, an autosomal recessive subtype of connective tissue disorder within the spectrum of Ehlers-Danlos syndrome (EDS), named classical-like EDS type 2 (clEDS2), was identified. clEDS2 is associated with biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, specifically, affecting its aortic carboxypeptidase-like protein (ACLP) isoform. We described the 15th patient (13th family) diagnosed with clEDS2. This patient presented with notable similarities in phenotype to the documented cases, along with additional characteristics such as significant prematurity and short stature. An EDS sequencing panel-based analysis revealed homozygous AEBP1: NM_001129.5:c.2923del, p.Ala975Profs*22 likely pathogenic variants, and maternally inherited heterozygous COL11A1: NM_001854.4:c.1160A>G, p.Lys387Arg variant of uncertain significance in our patient. Upon comprehensive review of all previously reported clEDS2 patients, our patient exhibited the following overlapping phenotypes, including cutaneous features: hyperextensibility, atrophic scars/delayed wound healing (100%), easy bruising (100%), excessive skin (93%); skeletal features: generalized joint hypermobility (93%), pes planus (93%), dislocation/subluxation (93%); and cardiovascular features (86%). Our patient did not display symptoms of the critical complications reported in a few individuals, including superior mesenteric artery aneurysms and ruptures, aortic root aneurysm/dissection, spontaneous pneumothoraxes, and bowel ruptures. Together, this case expands the genetic and clinical phenotypic spectrum of AEBP1-related clEDS2.

Keywords: Ehlers-Danlos syndrome; adipocyte enhancer binding protein 1 (AEBP1); aortic carboxypeptidase-like protein (ACLP); autosomal recessive; classical-like EDS type 2 (clEDS2); connective tissue disorders; prematurity; short stature.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Carboxypeptidases / genetics
Child
Ehlers-Danlos Syndrome* / genetics
Ehlers-Danlos Syndrome* / pathology
Female
Frameshift Mutation*
Homozygote*
Humans
Male
Pedigree
Phenotype
Repressor Proteins*

Substances

AEBP1 protein, human
Carboxypeptidases
Repressor Proteins

Grants and funding

MESL is an Investigator Grant Award Program (IGAP)-funded Clinician Scientist within the BC Children’s Hospital Research Institute. The grant number is F15-05673.