Whole Exome Sequencing Provides the Correct Diagnosis in a Case of Osteopathia Striata with Cranial Sclerosis: Case Report of a Novel Frameshift Mutation in AMER1

Abstract

The diagnosis of rare diseases with multisystem manifestations can constitute a difficult process that delays the determination of the underlying cause. Whole exome sequencing (WES) provides a suitable option to examine multiple target genes associated with several disorders that display common features. In this study, we report the case of a female patient suspected of having Sotos syndrome. Screening for the initially selected genes, considering Sotos syndrome and Sotos-like disorders, did not identify any pathogenic variants that could explain the phenotype. The extended analysis, which considered all genes in the exome associated with features consistent with those shown by the studied patient, revealed a novel frameshift variant in the AMER1 gene, responsible for osteopathia striata with cranial sclerosis. WES analysis and an updated revision of previously reported disease-causing mutations, proved useful to reach an accurate diagnosis and guide further examination to identify critical abnormalities.

Keywords

AMER1 - osteopathia striata with cranial sclerosis - macrocephaly - whole exome sequencing

Ethical Approval

This study was approved by the Ethics Committee of Research and Drugs from the hospital institution (Virgen de Altagracia Hospital, Manzanares, Spain).

Publikationsverlauf

Eingereicht: 03. Dezember 2019

Angenommen: 17. März 2020

Artikel online veröffentlicht:
21. April 2020

• References

• 1 Jenkins ZA, van Kogelenberg M, Morgan T. et al. Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet 2009; 41 (01) 95-100
• 2 Herman SB, Holman SK, Robertson SP, Davidson L, Taragin B, Samanich J. Severe osteopathia striata with cranial sclerosis in a female case with whole WTX gene deletion. Am J Med Genet A 2013; 161A [phone]
• 3 Fujita A, Ochi N, Fujimaki H. et al. A novel WTX mutation in a female patient with osteopathia striata with cranial sclerosis and hepatoblastoma. Am J Med Genet A 2014; 164A [phone]
• 4 Holman SK, Morgan T, Baujat G. et al. Osteopathia striata congenita with cranial sclerosis and intellectual disability due to contiguous gene deletions involving the WTX locus. Clin Genet 2013; 83 (03) 251-256
• 5 Joseph DJ, Ichikawa S, Econs MJ. Mosaicism in osteopathia striata with cranial sclerosis. J Clin Endocrinol Metab 2010; 95 (04) 1506-1507
• 6 Holman SK, Daniel P, Jenkins ZA. et al. The male phenotype in osteopathia striata congenita with cranial sclerosis. Am J Med Genet A 2011; 155A (10) 2397-2408
• 7 Hague J, Delon I, Brugger K. et al. Male child with somatic mosaic Osteopathia striata with cranial sclerosis caused by a novel pathogenic AMER1 frameshift mutation. Am J Med Genet A 2017; 173 (07) 1931-1935
• 8 Rivera MN, Kim WJ, Wells J. et al. The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity. Proc Natl Acad Sci U S A 2009; 106 (20) 8338-8343
• 9 Camp ND, James RG, Dawson DW. et al. Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein. J Biol Chem 2012; 287 (09) 6539-6550
• 10 Sperotto F, Bisogno G, Opocher E. et al. Osteopathia striata with cranial sclerosis and Wilms tumor: coincidence or consequence?. Clin Genet 2017; 92 (06) 674-675
• 11 Tanneberger K, Pfister AS, Brauburger K. et al. Amer1/WTX couples Wnt-induced formation of PtdIns(4,5)P2 to LRP6 phosphorylation. EMBO J 2011; 30 (08) 1433-1443
• 12 Tanneberger K, Pfister AS, Kriz V, Bryja V, Schambony A, Behrens J. Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1). J Biol Chem 2011; 286 (22) 19204-19214
• 13 Grohmann A, Tanneberger K, Alzner A, Schneikert J, Behrens J. AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane. J Cell Sci 2007; 120 (Pt 21): 3738-3747
• 14 Comai G, Boutet A, Tanneberger K. et al. Genetic and molecular insights into genotype-phenotype relationships in osteopathia striata with cranial sclerosis (OSCS) through the analysis of novel mouse Wtx mutant alleles. J Bone Miner Res 2018; 33 (05) 875-887
• 15 Zhang Z, Akyildiz S, Xiao Y. et al. Structures of the APC-ARM domain in complexes with discrete Amer1/WTX fragments reveal that it uses a consensus mode to recognize its binding partners. Cell Discov 2015; 1: 15016
• 16 Perdu B, Lakeman P, Mortier G, Koenig R, Lachmeijer AM, Van Hul W. Two novel WTX mutations underscore the unpredictability of male survival in osteopathia striata with cranial sclerosis. Clin Genet 2011; 80 (04) 383-388
• 17 Enomoto Y, Tsurusaki Y, Harada N, Aida N, Kurosawa K. Novel AMER1 frameshift mutation in a girl with osteopathia striata with cranial sclerosis. Congenit Anom (Kyoto) 2018; 58 (04) 145-146
• 18 Perdu B, de Freitas F, Frints SG. et al. Osteopathia striata with cranial sclerosis owing to WTX gene defect. J Bone Miner Res 2010; 25 (01) 82-90
• 19 König R, Dukiet C, Dörries A, Zabel B, Fuchs S. Osteopathia striata with cranial sclerosis: variable expressivity in a four generation pedigree. Am J Med Genet 1996; 63 (01) 68-73
• 20 O'Byrne JJ, Phelan E, Steenackers E, van Hul W, Reardon W. Germline mosaicism in osteopathia striata with cranial sclerosis--recurrence in siblings. Clin Dysmorphol 2016; 25 (02) 45-49
• 21 Zicari AM, Tarani L, Perotti D. et al. WTX R353X mutation in a family with osteopathia striata and cranial sclerosis (OS-CS): case report and literature review of the disease clinical, genetic and radiological features. Ital J Pediatr 2012; 38: 27
• 22 Pellegrino JE, McDonald-McGinn DM, Schneider A, Markowitz RI, Zackai EH. Further clinical delineation and increased morbidity in males with osteopathia striata with cranial sclerosis: an X-linked disorder?. Am J Med Genet 1997; 70 (02) 159-165
• 23 Bueno AL, Ramos FJ, Bueno O, Olivares JL, Bello ML, Bueno M. Severe malformations in males from families with osteopathia striata with cranial sclerosis. Clin Genet 1998; 54 (05) 400-405
• 24 Ciceri S, Cattaneo E, Fossati C, Radice P, Selicorni A, Perotti D. First evidence of vertical paternal transmission of osteopatia striata with cranial sclerosis. Am J Med Genet A 2013; 161A [phone]
• 25 Keymolen K, Bonduelle M, De Maeseneer M, Liebaers I. How to counsel in osteopathia striata with cranial sclerosis. Genet Couns 1997; 8 (03) 207-211
• 26 Savarirayan R, Nance J, Morris L, Haan E, Couper R. Osteopathia striata with cranial sclerosis: highly variable phenotypic expression within a family. Clin Genet 1997; 52 (04) 199-205