Primary muscle involvement in a 15‐year‐old girl with the recurrent homozygous c.362dupC variant in FKBP14

Abstract

Kyphoscoliotic Ehlers‐Danlos syndrome associated with FKBP14 (FKBP14‐kEDS) is an ultrarare autosomal recessive disorder reported in less than 30 individuals so far. In its original description, emphasis was put on the mild muscle involvement. Further reports confirm that FKBP14‐kEDS is distinguishable from primary muscle disorders by the lack of progressive muscle disease. We report a 15‐year‐old girl with FKBP14‐kEDS as a result of the recurrent c.362dupC variant, who also showed severe involvement of the lower limb muscles. She never attained autonomous walking and presented significant lower limb weakness. Lower limb magnetic resonance imaging showed a pattern of multiple muscle involvement. Further musculoskeletal assessment revealed significant bone mass density reduction of the spine, unilateral congenital hip dysplasia, and occipitoatlantoaxial instability. This patient points out the existence of a wider phenotypic spectrum of FKBP14‐kEDS to include early onset muscle disease.

Kyphoscoliotic Ehlers‐Danlos syndrome caused by pathogenic variants in FKBP14 : Further insights into the phenotypic spectrum and pathogenic mechanisms

“…hyperextensibility) (Kirschner et al, 2005;Voermans et al, 2008;Bönnemann, 2011). In kEDS-FKBP14 muscle weakness does not seem to progress and muscle MRI shows unspecific changes of myopathy (Baumann et al, 2012;Castori et al, 2018;Dordoni et al, 2016;Giunta et al, 2018). ously (Baumann et al, 2012), and is confirmed in this report.…”

“…This study reports the clinical and molecular characteristics of three nonrelated individuals with kEDS-FKBP14 and brings the total number of reported individuals to 40 individuals from 36 families (Alazami et al, 2016;Aldeeri et al, 2014;Bursztejn et al, 2017;Castori et al, 2018;Conversano et al, 2020;Dordoni et al, 2016;Giunta et al, 2018;Murray et al, 2014;Ruiz-Botero et al, 2019;Sainio et al, 2022;Semyachkina et al, 2021). Mild to moderate learning problems and/or speech problems have been reported in 22.5% (n = 9) and notably, 77.8% of these individuals (n = 7, not reported in 1 and absent in 1) also had hearing impairment which could negatively influence language development.…”

“…In 2012, Baumann et al (2012) first reported six individuals with a phenotype very similar to kEDS-PLOD1 (but with normal LP/HP ratios) in whom biallelic pathogenic variants in FKBP14, encoding the peptidyl-prolyl cis-trans isomerase family FK506-binding protein 22kDa (FKBP22), were identified. Since then, 37 individuals from 33 families with kEDS-FKBP14 (MIM# 614557) have been reported in literature (Alazami et al, 2016;Aldeeri et al, 2014;Bursztejn et al, 2017;Castori et al, 2018;Conversano et al, 2020;Dordoni et al, 2016;Giunta et al, 2018;Murray et al, 2014;Ruiz-Botero et al, 2019;Sainio et al, 2022;Semyachkina et al, 2021).…”

Genome analysis and knowledge-driven variant interpretation with TGex

“…TGex is designed to judiciously leverage the vast GeneCards Suite knowledgebase to address various clinical genetics requirements and workflows. TGex was shown to quickly identify causal mutations of rare disease cases, both when the causal variant was previously documented [72], and in the discovery of novel mutations through prioritization of potential variants of uncertain significance (VOUSes) [73]. Even for patients diagnosed with a known genetic disorder and an identified mutation, TGex has been used to examine phenotypic variability and identify modifier mutations and genes on top of established findings [74].…”

“…In the past few years, TGex and VarElect have been widely adopted for clinical genetics analysis in various academic institutions, genetic medical centers and hospitals world-wide, with usage volumes ranging from research groups focusing on a handful of patients to genetic centers routinely analyzing hundreds of cases per month [54, 72–78, 80–95]. Our interactions with a diversity of clinical genetics users impel us to deliver frequent community-driven improvements.…”