Clinical findings and molecular diagnosis in children with
Bardet-Biedl Syndrome in Turkey: Identification of novel
variants

Agaoglu, Nihat Bugra; Akgun-Dogan, Ozlem

doi:10.4274/gulhane.galenos.2021.73745

Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants

Özlem AKGÜN DOĞAN, (Ümraniye Eğitim ve Araştırma Hastanesi, Genomik Laboratuvarı (glab), İstanbul, Türkiye)

Nihat Buğra AĞAOĞLU (Ümraniye Eğitim ve Araştırma Hastanesi, Genomik Laboratuvarı (glab), İstanbul, Türkiye)

Gülhane Tıp Dergisi

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Yıl: 2022 Cilt: 64 Sayı: 2 Sayfa Aralığı: 144 - 151 Metin Dili: İngilizce DOI: 10.4274/gulhane.galenos.2021.73745 İndeks Tarihi: 19-07-2022

Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants

Öz:

Aims: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy with multisystemic involvement and variable phenotypic features. A diagnosis is usually made through the clinical diagnostic criteria. However, the clinical diagnosis can be difficult due to the absence of clear phenotype-genotype correlation and overlapping findings with other ciliopathies. Nextgeneration sequencing (NGS) is a rapid and cost-effective diagnostic method for this group of diseases. Besides correct diagnosis, detection of novel variants also contributes to establishing new phenotype-genotype correlations and delineating the pathophysiology of the syndrome. Here, we aimed to present clinical and molecular findings of patients with BBS using NGS panel analysis to contribute to the genotype-phenotype correlation in this rare syndrome. Methods: We retrospectively reviewed the medical records of patients with a suspicion of BBS admitted to the Pediatric Genetics Department in Umraniye Training and Research Hospital. Patients who met the BBS clinical diagnostic criteria were included in the study. Targeted NGS analysis, including 20 genes associated with BBS, was performed on an Illumina Next-Seq-500 platform. Results: The final analyses included 6 patients (age, mean±standard deviation: 14.3±6.6 years, female: 50%). Rod cone dystrophy (100%), polydactyly (100%), and intellectual disability (100%) were the most common findings followed respectively by obesity (83%), renal anomalies (83%), liver anomalies (67%), dental problems (67%), metabolic problems (50%), genital anomalies (33%), psychiatric disorders (33%), and sleep apnea (33%). The 5th metatarsal shortness and camptodactyly were anomalies reported for the first time in BBS. Seven variants were detected in the BBS1, BBS7, BBS5, BBS9, and MKKS, two of which were novel. BBS7 was the most common gene. Conclusions: Our study expanded the genotypic spectrum of the disease with two novel variants reported. Besides, by defining novel/rare clinical features, including camptodactyly, the fifth metatarsal, the 4th-5th metacarpal shortness, and nephrocalcinosis, it formed a source for the phenotype-genotype correlation trying to be established in the literature.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Ece Solmaz A, Onay H, Atik T, et al. Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes. Eur J Med Genet. 2015;58:689-694.
2. Deveault C, Billingsley G, Duncan JL, et al. BBS genotypephenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition. Hum Mutat. 2011;32:610- 619.
3. Forsythe E, Beales PL. Bardet-Biedl syndrome. Eur J Hum Genet. 2013;21:8-13.
4. Beales PL, Katsanis N, Lewis RA, et al. Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci. Am J Hum Genet. 2001;68:606-616. Erratum in: Am J Hum Genet. 2001;69:922.
5. Beales PL, Badano JL, Ross AJ, et al. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet. 2003;72:1187-1199.
6. Jeziorny K, Antosik K, Jakiel P, Młynarski W, Borowiec M, Zmysłowska A. Next-Generation Sequencing in the Diagnosis of Patients with Bardet-Biedl Syndrome-New Variants and Relationship with Hyperglycemia and Insulin Resistance. Genes (Basel). 2020;11:1283.
7. Reiter JF, Leroux MR. Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol. 2017;18:533- 547.
8. Niederlova V, Modrak M, Tsyklauri O, Huranova M, Stepanek O. Meta-analysis of genotype-phenotype associations in Bardet-Biedl syndrome uncovers differences among causative genes. Hum Mutat. 2019;40:2068-2087.
9. Forsyth RL, Gunay-Aygun M. Bardet-Biedl Syndrome Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews (R). Seattle (WA); 1993.
10. Mujahid S, Hunt KF, Cheah YS, et al. The Endocrine and Metabolic Characteristics of a Large Bardet-Biedl Syndrome Clinic Population. J Clin Endocrinol Metab. 2018;103:1834- 1841.
11. Gumus E, Tuncez E, Oz O, Saka Guvenc M. Clinical and exome sequencing findings in seven children with BardetBiedl syndrome from Turkey. Ann Hum Genet. 2021;85:27-36.
12. Warburg M, Riise R. Bardet-Biedl and Cohen syndromes: differential diagnostic criteria. J Med Genet. 2000;37:E46.
13. Zmyslowska A, Borowiec M, Antosik K, et al. Genetic evaluation of patients with Alström syndrome in the Polish population. Clin Genet. 2016;89:448-453.
14. Sözeri B, Demir F, Sonmez HE, et al. Comparison of the clinical diagnostic criteria and the results of the next-generation sequence gene panel in patients with monogenic systemic autoinflammatory diseases. Clin Rheumatol. 2021;40:2327- 2337.
15. Demir F, Dogan ÖA, Demirkol YK, et al. Genetic panel screening in patients with clinically unclassified systemic autoinflammatory diseases. Clin Rheumatol. 2020;39:3733- 3745.
16. Nykamp K, Anderson M, Powers M, et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med. 2017;19:1105-1117.
17. Stoetzel C, Laurier V, Davis EE, et al. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet. 2006;38:521-524.
18. M’Hamdi O, Redin C, Stoetzel C, et al. Clinical and genetic characterization of Bardet-Biedl syndrome in Tunisia: defining a strategy for molecular diagnosis. Clin Genet. 2014;85:172- 177.
19. Chen J, Smaoui N, Hammer MB, et al. Molecular analysis of Bardet-Biedl syndrome families: report of 21 novel mutations in 10 genes. Invest Ophthalmol Vis Sci. 2011;52:5317-5324.
20. Smaoui N, Chaabouni M, Sergeev YV, et al. Screening of the eight BBS genes in Tunisian families: no evidence of triallelism. Invest Ophthalmol Vis Sci. 2006;47:3487-3495.
21. Abu Safieh L, Aldahmesh MA, Shamseldin H, et al. Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping. J Med Genet. 2010;47:236-241.
22. Suspitsin EN, Imyanitov EN. Bardet-Biedl Syndrome. Mol Syndromol. 2016;7:62-71.
23. Bin J, Madhavan J, Ferrini W, Mok CA, Billingsley G, Héon E. BBS7 and TTC8 (BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population. Hum Mutat. 2009;30:E737-E746.
24. Moore SJ, Green JS, Fan Y, et al. Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study. Am J Med Genet A. 2005;132A:352-360.
25. O’Dea D, Parfrey PS, Harnett JD, Hefferton D, Cramer BC, Green J. The importance of renal impairment in the natural history of Bardet-Biedl syndrome. Am J Kidney Dis. 1996;27:776-783.
26. Imhoff O, Marion V, Stoetzel C, et al. Bardet-Biedl syndrome: a study of the renal and cardiovascular phenotypes in a French cohort. Clin J Am Soc Nephrol. 2011;6:22-29.
27. Forsythe E, Sparks K, Best S, et al. Risk Factors for Severe Renal Disease in Bardet-Biedl Syndrome. J Am Soc Nephrol. 2017;28:963-970.

APA	Akgun-Dogan O, Agaoglu N (2022). Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. , 144 - 151. 10.4274/gulhane.galenos.2021.73745
Chicago	Akgun-Dogan Ozlem,Agaoglu Nihat Bugra Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. (2022): 144 - 151. 10.4274/gulhane.galenos.2021.73745
MLA	Akgun-Dogan Ozlem,Agaoglu Nihat Bugra Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. , 2022, ss.144 - 151. 10.4274/gulhane.galenos.2021.73745
AMA	Akgun-Dogan O,Agaoglu N Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. . 2022; 144 - 151. 10.4274/gulhane.galenos.2021.73745
Vancouver	Akgun-Dogan O,Agaoglu N Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. . 2022; 144 - 151. 10.4274/gulhane.galenos.2021.73745
IEEE	Akgun-Dogan O,Agaoglu N "Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants." , ss.144 - 151, 2022. 10.4274/gulhane.galenos.2021.73745
ISNAD	Akgun-Dogan, Ozlem - Agaoglu, Nihat Bugra. "Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants". (2022), 144-151. https://doi.org/10.4274/gulhane.galenos.2021.73745

APA	Akgun-Dogan O, Agaoglu N (2022). Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. Gülhane Tıp Dergisi, 64(2), 144 - 151. 10.4274/gulhane.galenos.2021.73745
Chicago	Akgun-Dogan Ozlem,Agaoglu Nihat Bugra Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. Gülhane Tıp Dergisi 64, no.2 (2022): 144 - 151. 10.4274/gulhane.galenos.2021.73745
MLA	Akgun-Dogan Ozlem,Agaoglu Nihat Bugra Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. Gülhane Tıp Dergisi, vol.64, no.2, 2022, ss.144 - 151. 10.4274/gulhane.galenos.2021.73745
AMA	Akgun-Dogan O,Agaoglu N Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. Gülhane Tıp Dergisi. 2022; 64(2): 144 - 151. 10.4274/gulhane.galenos.2021.73745
Vancouver	Akgun-Dogan O,Agaoglu N Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants. Gülhane Tıp Dergisi. 2022; 64(2): 144 - 151. 10.4274/gulhane.galenos.2021.73745
IEEE	Akgun-Dogan O,Agaoglu N "Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants." Gülhane Tıp Dergisi, 64, ss.144 - 151, 2022. 10.4274/gulhane.galenos.2021.73745
ISNAD	Akgun-Dogan, Ozlem - Agaoglu, Nihat Bugra. "Clinical findings and molecular diagnosis in children with Bardet-Biedl Syndrome in Turkey: Identification of novel variants". Gülhane Tıp Dergisi 64/2 (2022), 144-151. https://doi.org/10.4274/gulhane.galenos.2021.73745