Disease: Myopathic Ehlers-Danlos Syndrome (mEDS)

Patient(s): 47 yo male, japanese descent

Variant: COL12A1 NM_004370.6: c.395-1G>A (Homozygous variant, at splice acceptor site in exon 6, causes in-frame skipping)(located in the genomic region encoding the first von Willebrand factor A domain)

Family: consanguineous parents with no related features of mEDS, healthy older brother

Phenotypes (Childhood): hypotonia, weak spontaneous movements, scoliosis, torticollis, soft plams, undescended testes, motor developmental delay, slender build, triangular face, short palpebral fissures, small nose, small mouth, large ears, bilateral knee dislocations, short stature.

Phenotypes (Adulthood): short stature, high palate, hypermobile small joints, deformed cervical spine, brachycephaly, bilateral long deformed 5th finger, severe scoliosis post surgical fixation, asymmetric pelvis

Classification: sequencing panel found the variant and it was confirmed through sanger sequencing.

According to ClinGenSVI recommendation: PVS1_Strong

Applicable criteria:

1) the one at a GT-AG 1,2 splice site

2) the one exerting exon skipping or use of a crypic splice site that preserved the reading frame.

3) the one at a truncated/altered region critical to protein function; was classified as PM3_Supporting (homozygous)

Variant not registered in gnomAD (PM2_Supporting)

Partial defect of first vWA in collagen XII judged as PS3

Disease: Von Willebrand Disease (VWD)

Patient(s): Found in 2 families

Variant: VWF NM_000552.5: c.2311A>G, p.(M771V Homozygous variant in exon 18 (VWF D' domain; 8 residues down from proteolytic VWFpp furin cleavage site)

Family: In family 1 there are 4 homozygous patients (2 male and 2 female), and one heterozygous patient (1 female). The affected females are denoted as person 1 and person 4 and the affected males are person 2 and person 3. There are three WT family members (1 female and 2 male), grandparents of these members are of unknown genotype including a daughter of an affected female and a WT male. Note here that in the family a p.R2663P variant has co-segregated with the above-mentioned variant but is not suspected to be the pathogenic driver of resulting bleeding tendency.

In family 2 the parents of the homozygous affected male are of unknown genotype. The affected male is denoted as person 7.

Phenotypes: Person 1- nose bleed, skin bleed, GI bleeding, oral cavity bleeds, Menorrhagia, muscle bleeding, and joint bleeding. Receives on-demand treatment for bleeding.

Person 2-Nose bleed, skin bleed, bleeding from small wounds, oral cavity bleeds, bleeding after tooth extraction, joint bleeding. Received prophylactic treatment, reduced to on-demand treatment after a few years.

Person 3-Nose bleed, skin bleed, oral cavity bleeds, bleeding after tooth extraction, muscle bleeding. Receives on-demand treatment for bleeding phenotype.

Person 4- Nose bleed, bleeding from small wounds, oral cavity bleed, bleeding after tooth extraction, joint bleeding. Received prophylactic treatment that was increased after her menarche.

Person 7- Nose bleed, oral cavity bleeds, bleeding after surgery or trauma, joint bleeding. Previously on prophylaxis, now managing bleeding with on-demand treatment.

Note that both the p.R2663P co-segregated variant and p.M771V variant are reported in NCBI dbSNP database but functional effect not yet established.

NGS confirmed the genotype of all study participants.

t and t, not T and T, because recessive