Case Report: First case of paternal mosaicism in Snijders Blok-Fisher syndrome

Snijders Blok-Fisher syndrome (SNIBFIS; OMIM #618604) is a rare autosomal dominant neurodevelopmental disorder caused mainly by de novo variants in POU3F3 gene. Here, we report for the first time, two affected siblings harboring a truncating POU3F3 variant inherited from their apparently unaffected father. Sanger sequencing across multiple tissues (blood, saliva, urine, and hair root samples) in the father together with RNA testing confirmed gonosomal mosaicism. Clinical re-evaluation of the father evidenced a previously unrecognized cognitive impairment. Conventional methods often fail to detect mosaic variants, highlighting the necessity to integrate integration of high-depth sequencing for precise risk evaluation. This work redefines the genetic architecture of SNIBFIS, emphasizing that comprehensive parental testing are indispensable for precise genetic counseling and family planning. The identification of mosaicism highlights the importance of increased clinical awareness, especially in families with more than one affected individual, and supports the use of comprehensive, high-resolution genetic testing strategies for accurate variant detection and characterization.