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Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability.

Smith, CEL; Laugel-Haushalter, V; Hany, U; Best, S; Taylor, RL; Poulter, JA; Wortmann, SB; Feichtinger, RG; Mayr, JA; Al Bahlani, S; et al. Smith, CEL; Laugel-Haushalter, V; Hany, U; Best, S; Taylor, RL; Poulter, JA; Wortmann, SB; Feichtinger, RG; Mayr, JA; Al Bahlani, S; Nikolopoulos, G; Rigby, A; Black, GC; Watson, CM; Mansour, S; Inglehearn, CF; Mighell, AJ; Bloch-Zupan, A; UK Inherited Retinal Disease Consortium, Genomics England Resear (2024) Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability. J Med Genet, 61 (7). pp. 689-698. ISSN 1468-6244 https://doi.org/10.1136/jmg-2023-109728
SGUL Authors: Mansour, Sahar

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Abstract

BACKGROUND: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease. METHODS: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice. RESULTS: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts. CONCLUSION: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.

Item Type: Article
Additional Information: © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
Keywords: Dentistry, Genetic Research, Genetics, Genetics, Medical, UK Inherited Retinal Disease Consortium, Genomics England Research Consortium, Dentistry, Dentistry, Genetic Research, Genetics, Genetics, Medical, 06 Biological Sciences, 11 Medical and Health Sciences, Genetics & Heredity
Journal or Publication Title: J Med Genet
ISSN: 1468-6244
Language: eng
Dates:
DateEvent
20 June 2024Published
8 March 2024Published Online
22 February 2024Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
PGS19-2/10111Rosetrees Trusthttp://dx.doi.org/10.13039/501100000833
UNSPECIFIEDRetina UKUNSPECIFIED
GR586Fight for Sight UKhttp://dx.doi.org/10.13039/501100000615
093113Wellcome Trusthttp://dx.doi.org/10.13039/100004440
PHRC 2008 No 4266 Amelogenesis ImperfectaFrench Ministry of HealthUNSPECIFIED
HUS, API, 2009–2012, ‘Development of the oral cavity: from gene to clinical phenotype in Human’University Hospital of StrasbourgUNSPECIFIED
ANR-10-LABX-0030-INRTAgence Nationale de la Recherchehttp://dx.doi.org/10.13039/501100001665
Project No 1.7European Regional Development Fundhttp://dx.doi.org/10.13039/501100008530
Project No 1.7European Reference NetworkUNSPECIFIED
E-GENODENTAgence Régionale de Santé Grand EstUNSPECIFIED
UNSPECIFIEDFilière TETECOUUNSPECIFIED
PubMed ID: 38458752
Web of Science ID: WOS:001181977900001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/116451
Publisher's version: https://doi.org/10.1136/jmg-2023-109728

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