RT Journal Article
SR Electronic
T1 Biallelic variants in Plexin B2 (<em>PLXNB2</em>) cause amelogenesis imperfecta, hearing loss and intellectual disability
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 689
OP 698
DO 10.1136/jmg-2023-109728
VO 61
IS 7
A1 Smith, Claire E L
A1 Laugel-Haushalter, Virginie
A1 Hany, Ummey
A1 Best, Sunayna
A1 Taylor, Rachel L
A1 Poulter, James A
A1 Wortmann, Saskia B
A1 Feichtinger, Rene G
A1 Mayr, Johannes A
A1 Al Bahlani, Suhaila
A1 Nikolopoulos, Georgios
A1 Rigby, Alice
A1 Black, Graeme C
A1 Watson, Christopher M
A1 Mansour, Sahar
A1 Inglehearn, Chris F
A1 Mighell, Alan J
A1 Bloch-Zupan, Agnès
A1 
YR 2024
UL http://jmg.bmj.com/content/61/7/689.abstract
AB 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.All data relevant to the study are included in the article or uploaded as supplementary information. Partial (anonymised) information can be provided on request.