Abstract
Brachydactyly refers to shortening of digits due to hypoplasia or aplasia of bones forming the hands and/or feet. Isolated brachydactyly type E (BDE), which is characterized by shortened metacarpals and/or metatarsals, results in a small proportion of patients from HOXD13 or PTHLH mutations, although in the majority of cases molecular lesion remains unknown. BDE, like other brachydactylies, shows clinical heterogeneity with highly variable intrafamilial and interindividual expressivity. In this study, we investigated two Polish cases (one familial and one sporadic) presenting with BDE and additional symptoms due to novel PTHLH mutations. Apart from BDE, the affected family showed short stature, mild craniofacial dysmorphism and delayed bone age. Sanger sequencing of PTHLH revealed a novel heterozygous frameshift mutation c.258delC(p.N87Tfs*18) in two affected individuals and one relative manifesting mild brachydactyly. The sporadic patient, in addition to BDE, presented with craniofacial dysmorphism, normal stature and bone age, and was demonstrated to carry a de novo heterozygous c.166C>T(p.R56*) mutation. Our paper reports on the two novel truncating PTHLH variants, resulting in variable combination of BDE and other symptoms. Data shown here expand the knowledge on the phenotypic presentation of PTHLH mutations, highlighting significant clinical variability and incomplete penetrance of the PTHLH-related symptoms.
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References
Mundlos, S. The brachydactylies: a molecular disease family. Clin. Genet. 76, 123–136 (2009).
Schwabe, G. C . & Mundlos, S. Genetics of Congenital Hand Anomalies. Handchir. Mikrochir. Plast. Chir. 36, 85–97 (2004).
Hertzog, K. P. Brachydactyly and pseudo-pseudohypoparathyroidism. Acta Genet. Med. Gemellol. 17, 428–438 (1968).
Caronia, G., Goodman, F. R., McKeown, C. M., Scambler, P. J. & Zappavigna, V. An I47L substitution in the HOXD13 homeodomain causes a novel human limb malformation by producing a selective loss of function. Development 130, 1701–1712 (2003).
Johnson, D., Kan, S. H., Oldridge, M., Trembath, R. C., Roche, P., Esnouf, R. M. et al. Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E. Am. J. Hum. Genet. 72, 984–997 (2003).
Klopocki, E., Hennig, B. P., Dathe, K., Koll, R ., de Ravel, T., Baten, E. et al. Deletion and point mutations of PTHLH cause brachydactyly type E. Am. J. Hum. Genet. 86, 434–439 (2010).
Maass, P. G., Wirth, J ., Aydin, A., Rump, A., Stricker, S., Tinschert, S. et al. A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly type E. Hum. Molec. Genet. 19, 848–860 (2010).
Brison, N ., Debeer, P., Fantini, S., Oley, C., Zappavigna, V., Luyten, F. P. et al. An N-terminal G11A mutation in HOXD13 causes synpolydactyly and interferes with Gli3R function during limb pre-patterning. Hum. Molec. Genet. 21, 2464–2475 (2012).
Jamsheer, A., Sowińska, A., Kaczmarek, L. & Latos-Bieleńska, A. Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report. BMC Med. Genet. 13, 4 (2012).
The 1000 Genomes Project. Available at http://www.1000genomes.org/. Accessed 9 December 2015.
The Database of Short Genetic Variation (dbSNP) National Center for Biotechnology Information. Available at http://www.ncbi.nlm.nih.gov/projects/SNP/snp_summary.cgi Accessed 9 December 2015.
The Exome Aggregation Consortium (ExAC). Available at http://exac.broadinstitute.org/. Accessed 9 December 2015.
The Human Gene Mutation Database. Available at http://www.hgmd.cf.ac.uk/ac/index.php. Accessed 9 December 2015.
NHLBI Exome Sequencing Project (ESP) Exome Varian Server (EVS). Available at http://evs.gs.washington.edu/EVS/. Accessed 9 December 2015.
Pereda, A., Garin, I ., Garcia-Barcina, M ., Gener, B., Beristain, E., Ibañez, A. M. et al. Brachydactyly E: isolated or as a feature of a syndrome. Orphanet J. Rare Dis. 8, 141 (2013).
Wang, J., Wang, Z., An, Y., Wu, C ., Xu, Y., Fu, Q. et al. Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature. Clin. Chim. Acta. 446, 9–14 (2015).
Acknowledgements
We are grateful to the patients for participating in this study. This research was supported by the National Centre for Research and Development grant LIDER/008/431/L-4/12/NCBR/2013 to AJ and by the Polish National Science Centre grants UMO-2011-03-B-NZ5-00510 and UMO-2011-03-D-NZ2-06136 to AJ.
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Jamsheer, A., Sowińska-Seidler, A., Olech, E. et al. Variable expressivity of the phenotype in two families with brachydactyly type E, craniofacial dysmorphism, short stature and delayed bone age caused by novel heterozygous mutations in the PTHLH gene. J Hum Genet 61, 457–461 (2016). https://doi.org/10.1038/jhg.2015.172
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DOI: https://doi.org/10.1038/jhg.2015.172
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