Autosomal dominant macrocephaly, acquired with impaired intellectual development: a report of an ultra-rare disease

Abstract Background Autism spectrum disorders affect social behavior and skills and are characterized by diverse etiology and additional findings. They are observed in approximately 1% of children, with heritability estimated to be 70–90%. Being highly heterogeneous, some of these conditions are caused by rare and ultra-rare genetic diseases that are often difficult to recognize. Timely diagnosis and proper genetic counseling are essential yet often insufficient for these families. Case presentation A family was referred to genetic counseling due to macrocephaly, drug-resistant epilepsy, and neurodevelopmental delay in a 13-year-old girl. During the genetic assessment, her 23-year-old brother was also noticed and taken into consideration due to macrocephaly and autism spectrum disorder. As the family first opted for whole-exome sequencing on their daughter only, a heterozygous likely pathogenic variant in the NFIB gene – c.115C > T, p.(Arg39Cys) was found. The gene is associated with the autosomal dominant condition macrocephaly, acquired with impaired intellectual development, OMIM #618286. The same variant was confirmed in her brother, excluding a de novo case. Unexpectedly, it was of maternal origin without any known phenotype expression in the mother. Conclusions This clinical case presents an ultra-rare condition characterized by variable expressivity, even intrafamilial. As exact genotype–phenotype correlations remain unknown, generating additional data from studies describing this disease is essential. Despite its rarity, the condition should be considered in cases of macrocephaly and neurodevelopmental delay or autistic features.