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) type 1

Patient(s): 13 yo, female and 14 yo, female, both Italian

Variant: VWF NM_000552.5: c.820A>C p. (Thr274Pro)

Dominant negative effect

Heterozygous carrier

Variant located in the D1 domain on VWF

Phenotypes:

heterozygous carriers have no bleeding history

reduced VWF levels compatible with diagnosis of VWD type 1

increased FVIII:C/VWF:Ag ratio, suggests reduced VWF synthesis/secretion as possible phathophysiological mechanism

Normal VWFpp/VWF:Ag ratio

Modest alteration of multimeric pattern in plasma and platelet multimers

plasma VWF showed slight increase of LMWM and decrease of IMWM and HMWM

Platelet VWF showed quantitative decrease of IMWM, HMWM, and UL multimers

In silico analysis:

SIFT, ALIGN, GVD Polyphen 2.0, SNP&GO, Mutation Taster, Pmut all suggest damaging consequences.

PROVEAN and Effect suggest neutral effect

according to ACMG guidelines this variant was classified as pathogenic