Effects of the Missense Variants on Complete Phenotype and Splicing Variant on Severe Growth Retardation in the <i>BPTF</i> Gene

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL, OMIM no #617755) is an ultra-rare syndrome associated with heterozygous pathogenic variants in the BPTF gene. Haploinsufficiency of the BPTF gene, a chromatin remodeling gene that is related to epigenetic modification, is the cause of this disease. BPTF gene variants were detected using whole-exome sequencing. Family segregation analysis was performed using sanger sequencing. This study reported three variants, c.2812+1G>C, c.6022G>A, and c.6416G>A in the BPTF gene. The variations of the c.6022G>A and c.2812+1G>C have not been previously reported in variant types observed at the BPTF gene in sources including Genome Aggregation Database (gnomAD), Leiden Open Variation Database (LOVD), Human Gene Mutation Database (HGMD), and ClinVar. We detected two novel missense variants in patients presenting all phenotypic characteristics of the BPTF-related NEDDFL syndrome severely, including severe ID, distinctive facial features, and anomalies of the hands and feet. Additionally, all four of our cases in this study had distal limb abnormalities such as syndactyly and clinodactyly that accompany severe intellectual disability. We suggest that distal limb abnormalities associated with the BPTF gene may accompany a more severe diagnosis of intellectual disability. Also, growth retardation may be more severe, especially for the cases with splicing variants of the BPTF gene variants.