Three generation families: Analysis of de novo variants in autism.

This study looked at genetic changes across three generations in 33 Brazilian families with autism. Researchers found that children with autism had slightly more new genetic changes (not inherited from parents) compared to their parents and other children without autism. Most of these genetic changes came from fathers. When parents passed on their genetic changes to children with autism, many of these changes were in genes already linked to autism risk, suggesting these families may have recently developed autism-related genetic variants.

This Brazilian study examined genetic variants across three generations in 33 families affected by autism spectrum disorder (ASD). Researchers sequenced the complete protein-coding regions of DNA from probands (children with ASD), their parents, and grandparents (231 individuals total). They found that children with ASD had marginally higher rates of de novo variants (new genetic changes not inherited from parents) compared to their parents and control groups. Most de novo variants originated from fathers in both generations.

Notably, 40% of de novo variants in parents that were transmitted to children occurred in known or suspected ASD genes, suggesting these represent recently emerged risk variants. The study identified three potential new ASD candidate genes: ZNF536, MSL2, and HDAC9.

This research reinforces the importance of de novo genetic variants in autism risk assessment. The finding of recently emerged family-specific risk variants suggests genetic counseling should consider multi-generational analysis. However, clinical application requires validation in larger, more diverse populations before implementation in routine practice.

Small sample size of 33 families from a single population may limit generalizability. The study acknowledges that sample size constraints may have prevented detection of enrichment patterns or sex bias effects. Results are specific to a Brazilian cohort and may not apply to other populations.

De novo variants (DNVs) analysis has proven to be a powerful approach to gene discovery in Autism Spectrum Disorder (ASD), which has not yet been shown in a Brazilian ASD cohort. The relevance of inherited rare variants has also been suggested, particularly in oligogenic models. We hypothesized that three-generation analyses of DNVs could provide new insights into the relevance of de novo and inherited variants across generations. To accomplish this goal, we performed whole-exome sequencing of 33 septet families composed of probands, parents, and grandparents (n = 231 individuals) and compared DNV rates (DNVr) between generations and those from two control cohorts.

The DNVr in the probands (DNVr = 1.16) was marginally higher than in parents (DNVr = 0.60; p = 0.054), and in controls (DNVr = 0.68; p = 0.035, congenital heart disorder and DNVr = 0.70; p = 0.047, unaffected ASD siblings from Simons Simplex Collection). Moreover, most of the DNVs were found to have paternal origin in both generations (84.6%). Finally, we observed that 40% (6/15) of the DNVs in parents transmitted for probands are in ASD or ASD candidate genes, representing recently emerged risk variants to ASD in their families and suggest ZNF536, MSL2 and HDAC9 as ASD candidate genes. We did not observe an enrichment of risk variants nor sex bias of transmitted variants in the three generations, that can be due to sample size.

These results further reinforce the relevance of de novo variants in ASD.