Ehlers Danlos syndrome with a likely monogenic cause

Gene: FLNA

Green List (high evidence)

PMID: 34863227 Billon et al., 2021
Summary report of 3 patient cohorts: 10 French female index cases from the Rare Vascular Diseases Centre, aged 14-66, 23 cases from the filaminopathies diagnostic lab, and a literature review of 59 cases - total of 92 cases with monoallelic variants in FLNA and periventricular nodular heterotopia type 1 (X-linked dominant).
50% of patients did not have neurological symptoms. Most patients presented with combined cardiovascular (CV) and connective tissue disorder (CTD) features. CV anomalies, e.g. aortic aneurysm and/or dilation, were present in 75% of patients. CTD features were present in 75% of patients - e.g. joints hyperlaxity and skin hyperelasticity.

Studies analysed in the literature review: PMIDs:11532987;15249610;15459826;15668422;15994863;15994863;16303888;16684786;19917821;20014127;20730588;20888935;21194575;21960593;22238415;22366253;23032111;24906659;26059841;27091362;27144976;27739212;28177866;28457522;29334594;29449050;30089473;30547349

PMID: 15668422 Sheen et al., 2005 - first report
2 families and 9 sporadic cases with periventricular nodular heterotopia associated with joint hyperlaxity, skin hyperelasticity, and aortic aneurysm/dissection. The authors suggested calling this condition Ehlers–Danlos variant of periventricular heterotopia.

FLNA is putatively linked to FG syndrome 2, 300321, and associated with 9 X-linked conditions: Cardiac valvular dysplasia, X-linked, 314400; Congenital short bowel syndrome, 300048; Frontometaphyseal dysplasia 1, 305620; Heterotopia, periventricular, 1, 300049; Intestinal pseudoobstruction, neuronal, 300048; Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I, 311300; Otopalatodigital syndrome, type II, 304120; Terminal osseous dysplasia, 300244 in OMIM (accessed 31st Oct 2025).

Created: 31 Oct 2025, 10:21 a.m. | Last Modified: 31 Oct 2025, 10:24 a.m.

Panel Version: 4.2

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Heterotopia, periventricular, 1, OMIM:300049

Publications

• 11532987
• 15249610
• 15459826
• 15668422
• 15994863
• 15994863
• 16303888
• 16684786
• 19917821
• 20014127
• 20730588
• 20888935
• 21194575
• 21960593
• 22238415
• 22366253
• 23032111
• 24906659
• 26059841
• 27091362
• 27144976
• 27739212
• 28177866
• 28457522
• 29334594
• 29449050
• 30089473
• 30547349
• 34863227

Red List (low evidence)

Cardiac valvular disease phenotype is not considered a strong enough overlap with connective tissue disorders for it to be included on this panel. It is green on FTAAD and familial non-syndromic congenital heart disease panels which seem more appropriate.

Created: 25 Jul 2017, 1:05 p.m.

Green List (high evidence)

Green List (high evidence)

Currently on R125 panel as well as other panels but I would argue that there is a connective tissue phenotype for a number of patients with missense variants in FLNA. A patient recently had R101 for connective tissue features, but went on to have R125 because of valvular disease and a FLNA pathogenic variant was identified. This is reasonable given the function of the protein Filamin A. Therefore, it would be beneficial for it to also be on R101 panel

Created: 8 Sep 2025, 10:50 a.m. | Last Modified: 8 Sep 2025, 10:50 a.m.

Panel Version: 4.2

Cardiac valvular dysplasia, X-linked;314400. Review from EDS National Diagnostic Service North West London Hospital NHS Trust: Dr Angela Brady FRCP PhD, Consultant Clinical Geneticist; Dr Neeti Ghali MBChB MD, Consultant Clinical Geneticist; Dr Fleur S van Dijk MD PhD, Consultant.

Created: 7 Jul 2017, 6:29 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
connective tissue phenotype eg. hypermobility, skin hyperextensibility, perforated ear drum, retinal detachment, arterial fragility, aortic dilatation, arterial tortuosity, valvular disease, PVL, lung

Publications

• 34863227
• 30089473
• 40883083
• 23032111

Red List (low evidence)

Review from Dr Anthony Vandersteen, IWK Health centre in Halifax, Nova Scotia 'fits better into PVNH syndrome rather than EDS, so should go into cortical dysplasia panel (the most expressed phenotype in those families), it is in some Familial thoracic aortic aneurysm and dissection  (TAAD) panels in the US but is primarily neurological phenotype.'

Created: 26 Apr 2017, 9:52 a.m.

Filamin A related EDS with periventricular nodular heterotopia associated to variants of FLNA is no longer to be included in the EDS spectrum (PMID:28306229)

Created: 19 Apr 2017, 7:57 a.m.

Publications

• 28306229