Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder.

Researchers found changes in a gene called ANKRD17 in two people with intellectual disability and autism-like features. When they studied mice with similar gene changes, the mice had problems with social behavior, learning, memory, and anxiety. The gene problems seem to affect how brain cells communicate and how they produce energy, which may explain the developmental challenges seen in affected individuals.

This study identified novel genetic variants in the ANKRD17 gene in two unrelated cases presenting with intellectual disability and autism spectrum disorder features. Case 1 involved a fetus with multiple congenital anomalies and a microdeletion affecting ANKRD17, while Case 2 was a 12-year-old male with mild intellectual disability and progressive social impairments carrying a specific ANKRD17 variant. Mouse model studies demonstrated that reduced ANKRD17 function led to social behavioral deficits, spatial learning and memory problems, and elevated anxiety. The research suggests these effects occur through disruptions to synaptic proteins and mitochondrial function, highlighting mitochondrial dysfunction as a key mechanism in ANKRD17-related neurodevelopmental disorders.

These findings expand genetic testing considerations for unexplained intellectual disability and ASD cases. The identification of mitochondrial dysfunction as a key mechanism suggests potential therapeutic avenues targeting cellular energy metabolism and synaptic function, though clinical applications require further validation.

Limited to two human cases and mouse model data. The abstract does not specify sample sizes for experimental studies or provide statistical analyses. Long-term outcomes and treatment implications remain unclear from this preliminary research.

ANKRD17 has recently been implicated in intellectual disability (ID) and autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. Using trio whole-exome sequencing (Trio-WES) and chromosomal microarray analysis (CMA), we identified two unrelated cases with novel de novo heterozygous ANKRD17 variants. Case 1 describes a fetus with multiple congenital anomalies, where genetic analysis revealed a microdeletion at 4q13.3 truncating the ANKRD17 gene. Case 2 involves a 12-year-old male presenting with mild ID and progressive social impairments, associated with a NM_032217.5: c.1252 C > T (p.Arg418*) variation in ANKRD17.

Our study highlighted in mouse models an association between Ankrd17 haploinsufficiency and deficits in social behavior, spatial learning and memory, as well as elevated anxiety. Furthermore, our studies suggest dysregulation of synaptic proteins and mitochondrial function, along with impaired neural circuits following Ankrd17 knockdown. These results expand the genetic and phenotypic spectrum of ANKRD17-related disorders, underscore the critical role of mitochondrial dysfunction in the pathophysiology of ANKRD17-related ID and ASD.