Siblings with vascular Ehlers‐Danlos syndrome inherited via maternal mosaicism

The vascular type of Ehlers-Danlos syndrome (vEDS; OMIM #130050) is the most severe type of EDS and is often life-threatening. It is an especially serious disorder due to premature death from major arterial tears and other severe complications, such as intestinal rupture and hematomas. Characteristic clinical features include a facial appearance, unusually thin but inextensible skin, and a tendency towards keloid scarring due to abnormal wound healing. This connective tissue disorder is usually caused by a heterozygous mutation of the COL3A1 that encodes type III collagen, with 50% of affected individuals inheriting the mutation from an affected parent, with the remaining 50% thought to arise de novo. However, mosaicism of parent is estimated to be 2% to 3%. Here we reported the mosaicism of vEDS in clinically asymptomatic mother of siblings with vEDS using next generation sequencing (NGS). Patient 1 is a 33-year-old Japanese woman. She was delivered at 36 weeks gestational age and her birth weight was 2120 g. There were no perinatal abnormalities. Development was normal. However, the patient experienced gastric rupture during the neonatal period despite the absence of the usual causative factors. At the age of 28 years, she experienced rupture of the heart during an operation for an aneurysm of the right subclavian artery. She had translucent skin. She had no extensibility of her skin or joints. She had a thin, pinched nose, prominent eyes, lobeless ears, and a lack of subcutaneous fat. Joint hypermobility was absent. Patient 2 was the younger brother of patient 1 by 6 years. He had no perinatal abnormalities. Development was normal. He experienced sigmoid colon rupture and small intestinal rupture at different times. He suffered many instances of muscle injury in different parts of the body. He presented with a similar skin and facial phenotype to that of his sister. He died suddenly at 24-years-old (cause unknown). The patients' parents have none of their children's symptoms and there is no other family history (Figure 1A). High resolution melting analysis for the patients revealed a different pattern (Figure S1) compared with those of their parents at exon 23 of COL3A1 in blood samples. Using Sanger sequencing, we detected a known pathogenic mutation at the splicing site of exon 23 (c.1662 + 1G > A, p.Gly537_Pro554del [NM_000090]) in patient 1 and patient 2 (Figure 1B). We did not find the same mutation in the blood samples of their parents (Figure 1B). After introducing NGS a few years later, the mosaicism was detected in a clinically asymptomatic mother using NGS (Supporting information S1). The detected allelic ratio of mother was 6.2% (129 / 2069) (Figure 1C). Details of methods were described in Supporting information S1. As with our patients and previous reports, NGS can be used to detect mosaicism and calculate mosaic ratios. Previous study reported identified mosaicism in a mother of a daughter with vEDS and a son with clinically suspected vEDS. The mother of siblings had some mild clinical symptoms of vEDS: thin and translucent skin, acrogeria, easy bruising, characteristic facial appearance, hypermobility of small joints with dislocations of the thumbs, and gingival recession. She had a higher rate of mosaicism for the pathogenic variant than the mother in the current report. In addition, she was also found to have the variant through Sanger sequencing. The distribution and proportion of cells containing pathogenic variants is random. Although no serious cases have been reported in low ratio mosaicism, it cannot be denied that connective tissues such as blood vessels may also be affected if the appearance, joint, and skin are characteristic. Early genetic diagnosis may enable targeted management to optimize both quality of life and prognosis for patients with mosaicism of COL3A1. We only performed tests on blood samples, but it is preferable to perform tests on other tissues for better confirmation. At present, if the child has autosomal dominant disease and the parents have no phenotype and the mutation has not been identified by Received: 1 September 2020 Revised: 30 November 2020 Accepted: 21 December 2020