Clinical and Molecular Spectrum of KBG Syndrome in the Largest Independent Turkish Cohort
18 affiliations
- 1Clinic of Medical Genetics, University of Health Sciences Türkiye, Ümraniye Training and Research Hospital, İstanbul, Türkiye
- 2Department of Pediatric Genetics, Ege University Faculty of Medicine, İzmir, Türkiye
- 3Department of Medical Genetics, İstanbul Medeniyet University Faculty of Medicine, İstanbul, Türkiye
- 4Clinic of Medical Genetics, University of Health Sciences Türkiye, Antalya Training and Research Hospital, Antalya, Türkiye
- 5Clinic of Pediatric Genetics, Konya City Hospital, Konya, Türkiye
- 6Department of Medical Genetics, Ordu University Training and Research Hospital, Ordu, Türkiye
- 7Department of Pediatric Genetics, University of Health Sciences Türkiye, Ümraniye Training and Research Hospital, İstanbul, Türkiye
- 8Department of Medical Genetics, Sakarya University Training and Research Hospital, Sakarya, Türkiye
- 9Clinic of Medical Genetics, University of Health Sciences Türkiye, Başakşehir Çam and Sakura City Hospital, İstanbul, Türkiye
- 10Department of Medical Genetics, Balıkesir University Faculty of Medicine, Balıkesir, Türkiye
- 11Department of Medical Genetics, Marmara University Faculty of Medicine, İstanbul, Türkiye
- 12Clinic of Medical Genetics, University of Health Sciences Türkiye, Zeynep Kamil Women and Children Diseases Training and Research Hospital, İstanbul, Türkiye
- 13Diagnoseq Laboratory, Ankara, Türkiye
- 14Division of Pediatric Genetic Diseases, Clinic of Pediatrics, University of Health Sciences Türkiye, Bursa City Hospital, Bursa, Türkiye
- 15Clinic of Medical Genetics, Dr. Ersin Arslan Training and Research Hospital, Gaziantep, Türkiye
- 16Clinic of Pediatric Genetics, University of Health Sciences Türkiye, Başakşehir Çam and Sakura City Hospital, İstanbul, Türkiye
- 17Clinic of Genetics, University of Health Sciences Türkiye, Kayseri State Hospital, Kayseri, Türkiye
- 18Department of Medical Genetics, İnönü University Faculty of Medicine, Malatya, Türkiye
Abstract
Background: KBG syndrome (OMIM #148050) is a rare autosomal dominant disorder caused by haploinsufficiency of ANKRD11 on chromosome 16q24.3. Populations outside Western Europe and North America remain underrepresented in the literature, and cohorts that comprehensively evaluate both sequence variants and copy-number variants (CNVs) remain limited.
Aims: To characterize the clinical and molecular spectrum of KBG syndrome associated with an identified ANKRD11 alteration in a Turkish multicenter cohort, investigate genotype–phenotype correlations, and assess the contributions of sequence variants and CNVs to disease diagnosis and variant interpretation.
Study Design: Multicenter, retrospective cohort study.
Methods: We retrospectively evaluated the clinical, anthropometric, and molecular characteristics of 36 Turkish individuals with KBG syndrome and an identified ANKRD11 alteration (31 pathogenic or likely pathogenic variants and five variants of uncertain significance) who were recruited from multiple pediatric genetics centers. Molecular analyses included whole-exome sequencing, clinical exome sequencing, and chromosomal microarray analysis (CMA). Variants were classified according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. An exploratory genotype-phenotype analysis was performed by comparing truncating, non-truncating sequence variant, and CNV/deletion groups using Fisher’s exact and Mann-Whitney U tests, with Benjamini-Hochberg correction for multiple comparisons.
Results: The cohort comprised 22 males and 14 females (male-to-female ratio, 1.57:1). A total of 29 distinct ANKRD11 alterations were identified, including 25 sequence variants and four distinct 16q24.3 deletions. Truncating variants were predominant (n = 25), while 11 sequence variants and four distinct 16q24.3 deletions further expanded the known molecular spectrum of KBG syndrome. The recurrent variant c.1903_1907del (p.Lys635GlnfsTer26) was identified in three unrelated individuals, supporting exon 9 as a major mutational hotspot. All three missense variants were clustered within the C-terminal degron, consistent with the previously reported enrichment of pathogenic missense variants in this functionally important region. 16q24.3 deletions accounted for 19.4% (7/36) of cases, underscoring the diagnostic value of copy-number analysis in patients with suspected KBG syndrome.
Conclusion: This study finding expand the clinical and molecular spectrum associated with ANKRD11, provide further evidence supporting haploinsufficiency as the primary disease mechanism, and underscore the diagnostic importance of CMA in syndromic neurodevelopmental disorders. Furthermore, integrating our cohort data with published findings provides a practical framework for interpreting ANKRD11 variants, particularly those involving the 5′ regulatory region and C-terminal missense variants.
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BibTeX
@article{kalay2026clinical,
title = {{Clinical and Molecular Spectrum of KBG Syndrome in the Largest Independent Turkish Cohort}},
author = {İrem Kalay and Tahir Atik and Elif Yılmaz Güleç and Aysel Ünal and Mine Balasar and Hayriye Nermin Keçeci and Çağrı Doğan and Esra Usluer and Burcu Yeter and Kübra Ateş and Alper Gezdirici and Hilmi Bolat and Kübra Taşar and Zeynep Esener and Esra Dirimtekin and Sümeyra Oğuz and Oğuzhan Bahadır and Süheyla Emre and Öznur Yılmaz Bayer and Abdullah İhsan Gürler and Uğur Gümüş and Yusuf Can Doğan and Serdar Bozlak and Halil İbrahim Yılmaz and Sema Nur Kır and Hilal Akalın and Aslıhan Kiraz and İbrahim Tekedereli and Munis Dündar},
journal = {Balkan Medical Journal},
year = {2026},
month = nov,
doi = {10.4274/balkanmedj.galenos.2026.2026-7-44},
url = {https://doi.org/10.4274/balkanmedj.galenos.2026.2026-7-44},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Clinical and Molecular Spectrum of KBG Syndrome in the Largest Independent Turkish Cohort
AU - İrem Kalay
AU - Tahir Atik
AU - Elif Yılmaz Güleç
AU - Aysel Ünal
AU - Mine Balasar
AU - Hayriye Nermin Keçeci
AU - Çağrı Doğan
AU - Esra Usluer
AU - Burcu Yeter
AU - Kübra Ateş
AU - Alper Gezdirici
AU - Hilmi Bolat
AU - Kübra Taşar
AU - Zeynep Esener
AU - Esra Dirimtekin
AU - Sümeyra Oğuz
AU - Oğuzhan Bahadır
AU - Süheyla Emre
AU - Öznur Yılmaz Bayer
AU - Abdullah İhsan Gürler
AU - Uğur Gümüş
AU - Yusuf Can Doğan
AU - Serdar Bozlak
AU - Halil İbrahim Yılmaz
AU - Sema Nur Kır
AU - Hilal Akalın
AU - Aslıhan Kiraz
AU - İbrahim Tekedereli
AU - Munis Dündar
PY - 2026
DA - 2026/11/02
JO - Balkan Medical Journal
DO - 10.4274/balkanmedj.galenos.2026.2026-7-44
UR - https://doi.org/10.4274/balkanmedj.galenos.2026.2026-7-44
AB - Background: KBG syndrome (OMIM #148050) is a rare autosomal dominant disorder caused by haploinsufficiency of ANKRD11 on chromosome 16q24.3. Populations outside Western Europe and North America remain underrepresented in the literature, and cohorts that comprehensively evaluate both sequence variants and copy-number variants (CNVs) remain limited. Aims: To characterize the clinical and molecular spectrum of KBG syndrome associated with an identified ANKRD11 alteration in a Turkish multicenter cohort, investigate genotype–phenotype correlations, and assess the contributions of sequence variants and CNVs to disease diagnosis and variant interpretation. Study Design: Multicenter, retrospective cohort study. Methods: We retrospectively evaluated the clinical, anthropometric, and molecular characteristics of 36 Turkish individuals with KBG syndrome and an identified ANKRD11 alteration (31 pathogenic or likely pathogenic variants and five variants of uncertain significance) who were recruited from multiple pediatric genetics centers. Molecular analyses included whole-exome sequencing, clinical exome sequencing, and chromosomal microarray analysis (CMA). Variants were classified according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. An exploratory genotype-phenotype analysis was performed by comparing truncating, non-truncating sequence variant, and CNV/deletion groups using Fisher’s exact and Mann-Whitney U tests, with Benjamini-Hochberg correction for multiple comparisons. Results: The cohort comprised 22 males and 14 females (male-to-female ratio, 1.57:1). A total of 29 distinct ANKRD11 alterations were identified, including 25 sequence variants and four distinct 16q24.3 deletions. Truncating variants were predominant (n = 25), while 11 sequence variants and four distinct 16q24.3 deletions further expanded the known molecular spectrum of KBG syndrome. The recurrent variant c.1903_1907del (p.Lys635GlnfsTer26) was identified in three unrelated individuals, supporting exon 9 as a major mutational hotspot. All three missense variants were clustered within the C-terminal degron, consistent with the previously reported enrichment of pathogenic missense variants in this functionally important region. 16q24.3 deletions accounted for 19.4% (7/36) of cases, underscoring the diagnostic value of copy-number analysis in patients with suspected KBG syndrome. Conclusion: This study finding expand the clinical and molecular spectrum associated with ANKRD11, provide further evidence supporting haploinsufficiency as the primary disease mechanism, and underscore the diagnostic importance of CMA in syndromic neurodevelopmental disorders. Furthermore, integrating our cohort data with published findings provides a practical framework for interpreting ANKRD11 variants, particularly those involving the 5′ regulatory region and C-terminal missense variants.
SN - 2146-3123
SN - 2146-3131
ER -