Clinical and molecular results in 15 Turkish patients with Wiedemann-Steiner syndrome: identification of eight novel KMT2A variants and a case of dual molecular diagnosis in the CSNK2A1.

UNLABELLED: Wiedemann-Steiner syndrome (WSS) is a rare autosomal dominant neurogenetic disorder caused by monallelic variants in KMT2A gene, characterized by neuromotor developmental delay, intellectual disability, microcephaly, seizures, behavioral disorders, dysmorphic facial features, hirsutism, and systemic anomalies. The KMT2A gene encodes a histone lysine methyltransferase crucial for the regulation of gene expression during early developmental stages. In this study, the clinical and molecular findings of 15 Turkish patients with WSS confirmed by whole exome sequencing are reported. Variant segregation was confirmed in all families. The ages of the patients were between 1.5 and 16 years. The majority of patients had neuromotor developmental delay, speech delay, and intellectual disability. The most frequently recognised dysmorphic facial features were thick eyebrows, long eyelashes, synophrys, hypertelorism, and broad nose. Other frequently observed clinical findings included short stature, congenital hypotonia, behavioral problems, genitourinary anomalies, and abnormal gait. Novel findings included focal segmental glomerulosclerosis, cholelithiasis, and sacrococcygeal teratoma. Fifteen different KMT2A variants were detected, including 8 novel (p.Gln3594*, p.Glu1407Argfs*4, p.Ser610Ilefs*9, p.Ser2188Leufs*25, p.Glu970Glnfs*37, p.Ser759Valfs*22, p.Lys1346Serfs*24, and c.11146 + 1_11146 + 6delinsA) variants. Additionally, one patient exhibited a dual molecular diagnosis with a de novo variant in CSNK2A1, associated with Okur-Chung neurodevelopmental syndrome.

CONCLUSION: This study expands the clinical and molecular spectrum of WSS, highlighting novel variants and unique manifestations. It emphasizes the importance of molecular testing in accurate diagnosis and management. By characterizing phenotypic diversity and dual diagnosis, this work contributes valuable insights for advancing clinical care and guiding future research.

WHAT IS KNOWN: • Wiedemann-Steiner syndrome (WSS) is a rare neurodevelopmental disorder caused by heterozygous KMT2A variants, characterized by developmental delay, intellectual disability, and distinctive facial features. • WSS exhibits marked clinical variability among affected individuals.

WHAT IS NEW: • This study presents the largest Turkish WSS cohort to date, expands the phenotypic spectrum with novel findings such as focal segmental glomerulosclerosis, cholelithiasis, and sacrococcygeal teratoma. • This study presents the largest Turkish WSS cohort to date and expands the phenotypic spectrum with novel findings such as focal segmental glomerulosclerosis, cholelithiasis, and sacrococcygeal teratoma, while also identifying eight novel WSS-associated variants, including p.Gln3594*, p.Glu1407Argfs*4, p.Ser610Ilefs*9, p.Ser2188Leufs*25, p.Glu970Glnfs*37, p.Ser759Valfs*22, p.Lys1346Serfs*24, and c.11146+1_11146+6delinsA.