Author(s) David J. Bunyan^1,2, David O. Robinson^1,2, Anthony G. Tyers³, Shuwen Huang⁴, Vivienne K. Maloney¹, Francis H. Grand², Sarah Ennis⁵, Samantha R. de Silva⁶, John A. Crolla^1,2, Tristan F. W. McMullan⁷

Affiliation(s)
¹ Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK.
² Human Genetics Division, Southampton University School of Medicine, Southampton, UK.
³ Ophthalmology Department, Salisbury District Hospital, Salisbury, UK.
⁴ Manchester Centre for Genomic Medicine, Saint Mary’s Hospital, Manchester, UK.
⁵ Genetic Epidemiology and Genomic Informatics Group, Faculty of Medicine, University of Southampton,Southampton, UK.
⁶ Oxford Eye Hospital, John Radcliffe Hospital, Oxford, UK.
⁷ Ophthalmology Department, Northampton General Hospital, Northampton, UK.

Abstract
Blepharoptosis (ptosis) is defined as the abnormal drooping of the upper eyelid and is a feature of many conditions. It can be in isolated or syndromic form, bilateral or unilateral and congenital or acquired. Previously we have carried out linkage analysis on a family with dominantly inherited congenital bilateral isolated ptosis and found the condition to be linked to a region of approximately 20 megabases of chromosome Xq24-Xq27.1 with a cumulative LOD score of 5.89. We now describe further analysis using array comparative genomic hybridisation (array CGH), fluorescence in situ hybridisation (FISH), long range PCR and sequencing. This has enabled us to identify and characterise at the level of DNA sequence an insertional duplication and rearrangement involving chromosomes 1p21.3 and a small quasipalindromic sequence in Xq27.1, disruption of which has been associated with other phenotypes but which is cosegregating with X-linked congenital bilateral isolated ptosis in this family. This work highlights the significance of the small quasipalindromic sequence in genomic rearrangements involving Xq27.1 and the importance of comprehensive molecular and molecular cytogenetic investigations to fully characterise genomic structural complexity.

Keywords
Ptosis, X-Linked Dominant, Insertional Duplication

Cite this paper
Bunyan, D. , Robinson, D. , Tyers, A. , Huang, S. , Maloney, V. , Grand, F. , Ennis, S. , Silva, S. , Crolla, J. and McMullan, T. (2014) X-Linked Dominant Congenital Ptosis Cosegregating with an Interstitial Insertion of a Chromosome 1p21.3 Fragment into a Quasipalindromic Sequence in Xq27.1. Open Journal of Genetics, 4, 415-425. doi: 10.4236/ojgen.2014.46039.

References

[1]   McMullan, T.F.W., Collins, A., Tyers, A.G. and Robinson, D.O. (2000) A Novel X Linked Truly Dominant Condition: X Linked Congenital Isolated Ptosis. American Journal of Human Genetics, 66, 1455-1460.
http://dx.doi.org/10.1086/302860

[2]   Engle, E.C., Castro, A.E., Macey, M.E., Knoll, J.H.M. and Beggs, A.H. (1997) A Gene for Isolated Congenital Ptosis Maps to a 3-cM Region within 1p32-p34. American Journal of Human Genetics, 60, 1150-1157.

[3]   Møller, R.S., Jensen, L.R., Maas, S.M., Filmus, J., Capurro, M., Hansen, C., et al. (2014) X-Linked Congenital Ptosis and Associated Intellectual Disability, Short Stature, Microcephaly, Cleft Palate, Digital and Genital Abnormalities Define Novel Xq25q26 Duplication Syndrome. Human Genetics, 133, 625-638.
http://dx.doi.org/10.1007/s00439-013-1403-3

[4]   Bowl, M.R., Nesbit, M.A., Harding, B., Levy, E., Jefferson, A., Volpi, E., et al. (2005) An Interstitial Deletion-Insertion Involving Chromosomes 2p25.3 and Xq27.1, near SOX3, Causes X-Linked Recessive Hypoparathyroidism. Journal of Clinical Investigations, 115, 2822-2831.
http://dx.doi.org/10.1172/JCI24156

[5]   Zhu, H., Shang, D., Sun, M., Choi, S., Liu, Q., Hao, J., et al. (2011) X-Linked Congenital Hypertrichosis Syndrome Is Associated with Interchromosomal Insertions Mediated by a Human-Specific Palindrome near SOX3. American Journal of Human Genetics, 88, 819-826.
http://dx.doi.org/10.1016/j.ajhg.2011.05.004

[6]   Schouten, J.P., McElgunn, C.J., Waaijer, R., Zwijnenburg, D., Diepvens, F. and Pals, G. (2002) Relative Quantification of 40 Nucleic Acid Sequences by Multiplex Ligation-Dependent Probe Amplification. Nucleic Acids Research, 30, e57.
http://dx.doi.org/10.1093/nar/gnf056

[7]   Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., et al. (2009) The Sequence Alignment/Map Format and SAM Tools. Bioinformatics, 25, 2078-2079.
http://dx.doi.org/10.1093/bioinformatics/btp352

[8]   Wang, K., Li, M. and Hakonarson, H. (2010) ANNOVAR: Functional Annotation of Genetic Variants from High-Throughput Sequencing Data. Nucleic Acids Research, 38, e164.
http://dx.doi.org/10.1093/nar/gkq603

[9]   Kleinjan, D.A. and van Heyningen, V. (2005) Long-Range Control of Gene Expression: Emerging Mechanisms and Disruption in Disease. American Journal of Human Genetics, 76, 8-32.
http://dx.doi.org/10.1086/426833

[10]   Sutton, E., Hughes, J., White, S., Sekido, R., Tan, J., Arboleda, V., et al. (2011) Identification of SOX3 as an XX Male Sex Reversal Gene in Mice and Humans. Journal of Clinical Investigations, 121, 328-341.
http://dx.doi.org/10.1172/JCI42580

[11]   Laumonnier, F., Ronce, N., Hamel, B.C., Thomas, P., Lespinasse, J., Raynaud, M., et al. (2002) Transcription Factor SOX3 Is Involved in X-Linked Mental Retardation with Growth Hormone Deficiency. American Journal of Human Genetics, 71, 1450-1455.
http://dx.doi.org/10.1086/344661

[12]   Collignon, J., Sockanathan, S., Hacker, A., Cohen-Tannoudji, M., Norris, D., Rastan, S., et al. (1996) A Comparison of the Properties of Sox-3 with Sry and Two Related Genes, Sox-1 and Sox-2. Development, 122, 509-520.

[13]   Fantes, J., Ragge, N.K., Lynch, S-A., McGill, N.I., Collin, J.R.O., Howard-Peebles, P.N., et al. (2003) Mutations in SOX2 Cause Anophthalmia. Nature Genetics, 33, 461-462.
http://dx.doi.org/10.1038/ng1120

[14]   Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., et al. (2001) The Putative Forkhead Transcription Factor FOXL2 Is Mutated in Blepharophimosis/Ptosis/Epicanthus Inversus Syndrome. Nature Genetics, 27, 159-166.
http://dx.doi.org/10.1038/84781

[15]   De Gregori, M., Ciccone, R., Magini, P., Pramparo, T., Gimelli, S., Messa, J., et al. (2007) Cryptic Deletions Are a Common Finding in “Balanced” Reciprocal and Complex Chromosome Rearrangements: A Study of 59 Patients. Journal of Medical Genetics, 44, 750-762.
http://dx.doi.org/10.1136/jmg.2007.052787

[16]   Edelmann, L., Spiteri, E., Koren, K., Pulijaal, V., Bialer, M.G., Shanske, A., et al. (2001) AT-Rich Palindromes Mediate the Constitutional t(11;22) Translocation. American Journal of Human Genetics, 68, 1-13.
http://dx.doi.org/10.1086/316952

[17]   Zlotorynski, E., Rahat, A., Skaug, J., Ben-Porat, N., Ozeri, E., Hershberg, R., et al. (2003) Molecular Basis for Expression of Common and Rare Fragile Sites. Molecular and Cellular Biology, 23, 7143-7151.
http://dx.doi.org/10.1128/MCB.23.20.7143-7151.2003

[18]   Hormozian, F., Schmitt, J.G., Sagulenko, E., Schwab, M. and Savelyeva, L. (2007) FRA1E Common Fragile Site Breaks Map within a 370 Kilobase Pair Region and Disrupt the Dihydropyrimidine Dehydrogenase Gene (DPYD). Cancer Letters, 246, 82-91.
http://dx.doi.org/10.1016/j.canlet.2006.02.004