RESUMEN

This is a case of a 46-year-old woman who presented with right common iliac artery dissection preceded by a left common iliac artery dissection and rupture 6 years earlier. Both iliac arteries required repair. Based on her presentation, she met the clinical diagnostic criteria for vascular Ehlers-Danlos syndrome; however, the genetic workup demonstrated that she had classic Ehlers-Danlos syndrome due to a null variant in COL5A1, which is rarely associated with arteriopathy.

RESUMEN

(1) Background: Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by joint hypermobility and skin hyperextensibility with atrophic scarring. Many cEDS individuals carry variants in either the COL5A1 or COL5A2 genes. Mosaicism is relatively common in heritable connective tissue disorders but is rare in EDS. In cEDS, a single example of presumed gonosomal mosaicism for a COL5A1 variant has been published to date. (2) Methods: An 8-year-old girl with cEDS was analyzed by next-generation sequencing (NGS). Segregation was performed by Sanger sequencing in her unaffected parents. In the father, the mosaicism of the variant was further analyzed by targeted NGS and droplet digital PCR (ddPCR) in the blood and by Sanger sequencing in other tissues. (3) Results: The NGS analysis revealed the novel germline heterozygous COL5A1 c.1369G>T, p.(Glu457*) variant in the proband. Sanger chromatogram of the father's blood specimen suggested the presence of a low-level mosaicism for the COL5A1 variant, which was confirmed by NGS and estimated to be 4.8% by ddPCR. The mosaicism was also confirmed by Sanger sequencing in the father's saliva, hair bulbs and nails. (4) Conclusions: We described the second case of cEDS caused by paternal gonosomal mosaicism in COL5A1. Parental mosaicism could be an issue in cEDS and, therefore, considered for appropriate genetic counseling.

Asunto(s)

Colágeno Tipo V/genética , Síndrome de Ehlers-Danlos/genética , Mosaicismo , Cromosomas Sexuales/genética , Niño , Codón sin Sentido , Análisis Mutacional de ADN , Femenino , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linaje

RESUMEN

BACKGROUND: Classical Ehlers-Danlos syndrome (cEDS) is a heterogeneous connective tissue disorder that mainly results from the germline mutation of COL5A1 and COL5A2. The majority of the COL5A2 mutations reported to date represent structural mutations, including missense or in-frame exon-skipping splice mutations. The only reported synonymous mutation was expected to affect on splicing of exon 29 by prediction programs which should be further confirmed. METHODS: Whole exome sequencing was performed to identify the genetic variants of a Chinese boy who was characterized by skin hyperextensibility, abnormal scarring, hypermobile joints and scoliosis. Sanger sequencing was used to validate the variants in his parents. Reverse transcription polymerase chain reaction (RT-PCR) was performed to analyze the functional effects of the variant. RESULTS: A de novo heterozygous synonymous variant (NM_000393.5:c.1977 G>A) of COL5A2 gene was identified in the patient. The results of RT-PCR revealed that the synonymous variant led to skipping of exon 29 in the RNA transcript. CONCLUSIONS: Our study supplies further supporting evidence that the synonymous COL5A2 mutation c.1977 G>A can cause skipping of exon 29 in the RNA transcript, thus resulting in the production of mutant α2(V)-chains and clinical phenotype of cEDS. This result highlights the need to include splicing-altering synonymous mutations into the screening for cEDS.

Asunto(s)

Colágeno Tipo V/genética , Síndrome de Ehlers-Danlos/genética , Niño , Colágeno Tipo V/metabolismo , Síndrome de Ehlers-Danlos/patología , Heterocigoto , Humanos , Masculino , Mutación , Empalme del ARN , Secuenciación del Exoma

RESUMEN

We report a 13-year-old male patient with severe orthopedic problems including features of a connective tissue disorder and a heterozygous c.305T > A variant found within exon 3 of the autosomal dominant collagen ( COL5A1 ) gene causing the classic Ehlers-Danlos syndrome. This variant has not been reported previously and identified as having an unknown clinical significance but classified as trending damaging per in silico prediction with high conservation among species. Our patient's father had the same gene variant and similar features of stretchable skin, easy bruising, and multiple joint dislocations. The father had unexplained heart failure requiring cardiac transplantation at 43 years of age.