A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings

Area of Science:

• Genetics
• Molecular Biology
• Rare Diseases

Background:

• Autosomal-recessive variants in the AEBP1 gene are linked to a novel connective tissue disorder (CTD).
• This CTD shares features with Ehlers-Danlos Syndrome (EDS) and the marfanoid spectrum.
• Clinical variability has been observed in previously reported individuals.

Purpose of the Study:

• To identify additional cases of AEBP1-associated CTD using unbiased high-throughput sequencing.
• To further elucidate the genetic mechanisms and clinical spectrum of this rare disorder.
• To highlight the utility of exome sequencing in diagnosing rare genetic conditions.

Main Methods:

• Clinical exome sequencing was employed to identify genetic variants.
• Segregation analysis and chromosomal microarray were used to confirm variant inheritance and homozygosity.
• RT-PCR was performed to investigate the molecular mechanism (nonsense-mediated mRNA decay).

Main Results:

• A homozygous nonsense variant (c.917dup, p.Tyr306*) in AEBP1 was identified in a previously unsolved CTD case.
• Segregation testing confirmed the variant in affected siblings and carrier status in the mother.
• RT-PCR supported a functional nullizygosity mechanism due to nonsense-mediated mRNA decay.
• Two individuals from a fourth family with AEBP1-associated CTD were identified.

Conclusions:

• Autosomal-recessive loss-of-function (LOF) variants in AEBP1 cause a CTD with features overlapping EDS subtypes and the marfanoid spectrum.
• Exome sequencing is a valuable tool for the rapid identification and diagnosis of rare genetic disorders like AEBP1-associated CTD.
• Further identification of affected individuals is crucial for comprehensive clinical characterization.