Genotypic and phenotypic spectrum of Galloway-Mowat syndrome in Kuwait

Abstract

Introduction:Galloway-Mowat syndrome (GAMOS) is a rare genetic disorder that is characterized by microcephaly and neurological and renal abnormalities. Ten types of GAMOS exist based on the underlying implicated gene. The purpose of this study was to investigate the phenotypic and genotypic spectrum of GAMOS in Kuwait. Methods:We queried the Kuwait Medical Genetic Center database for subjects with neuro-renal or neurological phenotypes and pathogenic variants in any of the ten known genes associated with GAMOS. Results:We identified eight subjects from five unrelated families with biallelic pathogenic WDR73 variants and a diagnosis of GAMOS type 1 (GAMOS1). All subjects had global developmental delay, microcephaly, tone abnormalities and impaired activities of daily living. Renal features were observed in more than half of the subjects (5/8 subjects) and included proteinuria, nephrotic syndrome, and end-stage renal disease (ESRD). More than half of the subjects (5/8 subjects) died by 5–10 due to ESRD, including one of which who died due to unknown cause while the rest (ages 3–5 years) are still living with no renal features. Two possible founder variants were identified, including c.287 G > A;p.Arg96Lys in three unrelated families of Kuwaiti, Iraqi, and/or Syrian ancestry, and c.767 G > A;p.Arg256Gln in two unrelated families of Kuwaiti or Syrian ancestry. Conclusion:GAMOS1 is the most prevalent form of GAMOS in Kuwait, likely due to the presence of two WDR73 regional founder variants. These findings contribute to the global understanding of GAMOS and highlight the important contribution of regional genetic studies in diverse populations to rare disease research.

Keywords

Galloway-Mowat syndrome / Biallelic / Autosomal recessive / Neuro-renal syndrome / Founder mutations / Kuwait / WDR73

Acknowledgments

We would like to thank the families for their participation in this study.

Author contribution

Fares Alhammad and Dana Marafi contributed to drafting the manuscript and revising it critically for important intellectual content. Nawal Y Ali, Sumaya Alkanderi, Reem Elshafie, Laila Bastaki, Hind Alsharhan, Buthina Albash, and Dana Marafi contributed to data acquisition including clinical examination of patients, clinical images, sample collection, and genetic counseling. Fares Alhammad, Hind Alsharhan, and Dana Marafi contributed to the analysis and interpretation of the data and critical review of the manuscript. All authors approved the final manuscript and agreed to be accountable for all aspects of the work.

Funding

No external funding was received for this work.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declaration of Competing Interest

Authors have no potential conflicts to report.

Appendix A. Supporting information

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.gmg.2026.100110.

References

[1] W.H. Galloway, A.P. Mowat, Congenital microcephaly with hiatus hernia and nephrotic syndrome in two sibs, J. Med. Genet. 5 (4) (1968) 319-321, https://doi.org/10.1136/jmg.5.4.319

[2] J. Vodopiutz, R. Seidl, D. Prayer, M.I. Khan, J.A. Mayr, B. Streubel, J.O. Steiß, A. Hahn, D. Csaicsich, C. Castro, M. Assoum, T. Müller, D. Wieczorek, G.M. Mancini, C.E. Sadowski, N. Lévy, A. Mégarbané, K. Godbole, D. Schanze, ... M. Zenker, WDR73 mutations cause infantile neurodegeneration and variable glomerular kidney disease , Hum. Mutat. 36 (11) (2015) 1021-1028, https://doi.org/10.1002/humu.22828

[3] Y. Yang, Y. He, L. Zhen, D.Z. Li, Fetal phenotype of Galloway—Mowat syndrome 3 caused by a specific OSGEP variant, Eur. J. Obstet. Gynecol. Reprod. Biol. 242 (2019) 182-184, https://doi.org/10.1016/j.ejogrb.2019.09.025

[4] J.O. Steiss, S. Gross, B.A. Neubauer, A. Hahn, Late—onset nephrotic syndrome and severe cerebellar atrophy in Galloway—Mowat syndrome, Neuropediatrics 36 (5) (2005) 332-335, https://doi.org/10.1055/s—2005—872842

[5] M. El Younsi, L. Kraoua, R. Meddeb, M. Ferjani, M. Trabelsi, I. Ouertani, F. Maazoul, N. Abid, T. Gargah, R. M’Rad, WDR73—related galloway mowat syndrome with collapsing glomerulopathy , Eur. J. Med. Genet. 62 (9) (2019) 103550, https://doi.org/10.1016/j.ejmg.2018.10.002

[6] C.—P. Chen, S.—P. Lin, Y.—P. Liu, J.—D. Tsai, C.—Y. Chen, S.—L. Shih, F.—J. Tsai, P.—C. Wu, W. Wang, Galloway—Mowat syndrome: prenatal ultrasound and perinatal magnetic resonance imaging findings, Taiwan. J. Obstet. Gynecol. 50 (2) (2011) 212-216, https://doi.org/10.1016/j.tjog.2011.04.005

[7] E. Colin, E. Huynh Cong, G. Mollet, A. Guichet, O. Gribouval, C. Arrondel, O. Boyer, L. Daniel, M.C. Gubler, Z. Ekinci, M. Tsimaratos, B. Chabrol, N. Boddaert, A. Verloes, A. Chevrollier, N. Gueguen, V. Desquiret—Dumas, M. Ferré, V. Procaccio, ... C. Antignac, Loss—of—function mutations in WDR73 are responsible for microcephaly and steroid—resistant nephrotic syndrome: Galloway—Mowat syndrome , Am. J. Hum. Genet 95 (6) (2014) 637-648, https://doi.org/10.1016/j.ajhg.2014.10.011

[8] E. Treimer, K. Niedermayer, S. Schumann, M. Zenker, M.J. Schmeisser, S.J. Kühl, Galloway—Mowat syndrome: new insights from bioinformatics and expression during Xenopus embryogenesis, Gene Expr. Patterns 42 (2021) 119215, https://doi.org/10.1016/j.gep.2021.119215

[9] R.N. Jinks, E.G. Puffenberger, E. Baple, B. Harding, P. Crino, A.B. Fogo, O. Wenger, B. Xin, A.E. Koehler, M.H. McGlincy, M.M. Provencher, J.D. Smith, L. Tran, S. Al Turki, B.A. Chioza, H. Cross, G.V. Harlalka, M.E. Hurles, R. Maroofian, ... K.A. Strauss, Recessive nephrocerebellar syndrome on the Galloway—Mowat syndrome spectrum is caused by homozygous protein—truncating mutations of WDR73 , Brain 138 (Pt 8) (2015) 2173-2190, https://doi.org/10.1093/brain/awv153

[10] J. Racine, R. Golden, A patient diagnosed with Galloway—Mowat syndrome presenting with a rod—cone functional anomaly with electronegative dark—adapted ERGs, Doc. Ophthalmol. 143 (1) (2021) 75-83, https://doi.org/10.1007/s10633—021—09820—4

[11] R.O. Rosti, E. Dikoglu, M.S. Zaki, G. Abdel—Salam, N. Makhseed, J.C. Sese, D. Musaev, B. Rosti, M.J. Harbert, M.C. Jones, K.K. Vaux, J.G. Gleeson, Extending the mutation spectrum for Galloway—Mowat syndrome to include homozygous missense mutations in the WDR73 gene , Am. J. Med. Genet. A 170a (4) (2016) 992-998, https://doi.org/10.1002/ajmg.a.37533

[12] M.A. Al—Rakan, M.D. Abothnain, M.T. Alrifai, M. Alfadhel, Extending the ophthalmological phenotype of Galloway—Mowat syndrome with distinct retinal dysfunction: a report and review of ocular findings, BMC Ophthalmol. 18 (1) (2018) 147, https://doi.org/10.1186/s12886—018—0820—4

[13] Y.L. Yang, H.F. Lee, C.S. Chi, C.R. Tsai, S.N. Liu, P.Y. Wu, Refining the phenotypic and genotypic spectrum of WDR73—related galloway—mowat syndrome: a case series and systematic review, Neurol. Genet 11 (4) (2025) e200280, https://doi.org/10.1212/nxg.0000000000200280

[14] T. Ben—Omran, S. Fahiminiya, N. Sorfazlian, M. Almuriekhi, Z. Nawaz, J. Nadaf, K.A. Khadija, S. Zaineddin, H. Kamel, J. Majewski, V. Tropepe, Nonsense mutation in the WDR73 gene is associated with Galloway—Mowat syndrome , J. Med. Genet. 52 (6) (2015) 381-390, https://doi.org/10.1136/jmedgenet—2014—102707

[15] C. Jiang, N. Gai, Y. Zou, Y. Zheng, R. Ma, X. Wei, D. Liang, L. Wu, WDR73 missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in a consanguineous family, Clin. Chim. Acta 464 (2017) 24-29, https://doi.org/10.1016/j.cca.2016.10.029

[16] J.K. Warejko, W. Tan, A. Daga, D. Schapiro, J.A. Lawson, S. Shril, S. Lovric, S. Ashraf, J. Rao, T. Hermle, T. Jobst—Schwan, E. Widmeier, A.J. Majmundar, R. Schneider, H.Y. Gee, J.M. Schmidt, A. Vivante, A.T. van der Ven, H. Ityel, ... F. Hildebrandt, Whole exome sequencing of patients with steroid—resistant nephrotic syndrome, Clin. J. Am. Soc. Nephrol. 13 (1) (2018) 53-62, https://doi.org/10.2215/cjn.04120417

[17] C. Xu, J. Min, Structure and function of WD40 domain proteins, Protein Cell 2 (3) (2011) 202-214, https://doi.org/10.1007/s13238—011—1018—1

[18] S. Laurie, W. Steyaert, E. de Boer, K. Polavarapu, N. Schuermans, A.K. Sommer, G. Demidov, K. Ellwanger, I. Paramonov, C. Thomas, S. Aretz, J. Baets, E. Benetti, G. Bullich, P.F. Chinnery, J. Clayton—Smith, E. Cohen, D. Danis, J.M. de Sainte Agathe, ... A. Hoischen, Genomic reanalysis of a pan—European rare—disease resource yields new diagnoses, Nat. Med. 31 (2) (2025) 478-489, https://doi.org/10.1038/s41591—024—03420—w

[19] D. Marafi, Founder mutations and rare disease in the Arab world, Dis. Model Mech. 17 (6) (2024), https://doi.org/10.1242/dmm.050715

[20] M. Aburezq, A. Alahmad, R. Alsafi, A. Al—Tawari, D. Ramadan, M. Shafik, O. Abdelaty, N. Makhseed, R. Elshafie, M. Ayed, A. Hayat, F. Dashti, D. Marafi, B. Albash, L. Bastaki, H. Alsharhan, Biotin—thiamine responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of cases in Kuwait with novel variants, Orphanet J. Rare Dis. 18 (1) (2023) 271, https://doi.org/10.1186/s13023—023—02888—y

[21] N.T. Alzayed, A.H. Alzuabi, R.A. Alqusaimi, E.A. El—Anany, A. Alholle, A.H. Aboelanine, S. Omar, R. Alsafi, A.A. Elmonairy, F.J. Alali, A. Alahmad, H. Alsharhan, B. Albash, D. Marafi, Tribal founder EMC1 variant in 5 Kuwaiti families expands phenotypic spectrum of EMC1—related disorder , Neurol. Genet. 10 (3) (2024) e200156, https://doi.org/10.1212/nxg.0000000000200156