Novel TNXB Variants in Two Italian Patients with Classical-Like Ehlers-Danlos Syndrome
by
Lucia Micale 1,*,†
, Vito Guarnieri 1,†, Bartolomeo Augello 1, Orazio Palumbo 1, Emanuele Agolini 2, Valentina Maria Sofia 2, Tommaso Mazza 3, Antonio Novelli 2, Massimo Carella 1 and Marco Castori 1
Lucia Micale 1,*,†, Vito Guarnieri 1,†, Bartolomeo Augello 1, Orazio Palumbo 1, Emanuele Agolini 2, Valentina Maria Sofia 2, Tommaso Mazza 3, Antonio Novelli 2, Massimo Carella 1 and Marco Castori 1
1
Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, 71043 San Giovanni Rotondo (Foggia), Italy
2
Laboratory of Medical Genetics, IRCCS-Bambino Gesù Children's Hospital, 00146 Rome, Italy
3
Unit of Bioinformatics, Fondazione IRCCS-Casa Sollievo della Sofferenza, 71043 San Giovanni Rotondo (Foggia), Italy
*
Author to whom correspondence should be addressed.
†
These authors equally contributed to the work.
Genes 2019, 10(12), 967; https://doi.org/10.3390/genes10120967
Received: 26 October 2019 / Revised: 19 November 2019 / Accepted: 21 November 2019 / Published: 25 November 2019
(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)
TNXB-related classical-like Ehlers-Danlos syndrome (TNXB-clEDS) is an ultrarare type of Ehlers-Danlos syndrome due to biallelic null variants in TNXB, encoding tenascin-X. Less than 30 individuals have been reported to date, mostly of Dutch origin and showing a phenotype resembling classical Ehlers-Danlos syndrome without atrophic scarring. TNXB-clEDS is likely underdiagnosed due to the complex structure of the TNXB locus, a fact that complicates diagnostic molecular testing. Here, we report two unrelated Italian women with TNXB-clEDS due to compound heterozygosity for null alleles in TNXB. Both presented soft and hyperextensible skin, generalized joint hypermobility and related musculoskeletal complications, and chronic constipation. In addition, individual 1 showed progressive finger contractures and shortened metatarsals, while individual 2 manifested recurrent subconjunctival hemorrhages and an event of spontaneous rupture of the brachial vein. Molecular testing found the two previously unreported c.8278C > T p.(Gln2760*) and the c.(2358 + 1_2359 − 1)_(2779 + 1_2780 − 1)del variants in Individual 1, and the novel c.1150dupG p.(Glu384Glyfs*57) and the recurrent c.11435_11524+30del variants in Individual 2. mRNA analysis confirmed that the c.(2358 + 1_2359 − 1)_(2779 + 1_2780 − 1)del variant causes a frameshift leading to a predicted truncated protein [p.(Thr787Glyfs*40)]. This study refines the phenotype recently delineated in association with biallelic null alleles in TNXB, and adds three novel variants to its mutational repertoire. Unusual digital anomalies seem confirmed as possibly peculiar of TNXB-clEDS, while vascular fragility could be more than a chance association also in this Ehlers-Danlos syndrome type.
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Keywords:
Classical-like; Ehlers-Danlos syndrome; haploinsufficiency; tenascin-X; TNXB
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MDPI and ACS Style
Micale, L.; Guarnieri, V.; Augello, B.; Palumbo, O.; Agolini, E.; Sofia, V.M.; Mazza, T.; Novelli, A.; Carella, M.; Castori, M. Novel TNXB Variants in Two Italian Patients with Classical-Like Ehlers-Danlos Syndrome. Genes 2019, 10, 967.
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