To date, all individuals diagnosed with CHEDDA have a de novo missense or indel sequence variant in the ‘HX repeat motif’ of ATN1 in exon 7. The HX repeat is a repetitive sequence motif where eight histidines are separated by one amino acid. All variants in CHEDDA disrupt the regular spacing of the histidine residues. Our study is supportive of other data consistent with ATN1 having a role as a key nuclear transcriptional regulator involved in the regulation of organ development, including the brain and heart and suggests a critical role of the ATN1 HX repeat motif in the control of human embryonic development which we are further investigating.
That the variants cause a simple haploinsufficiency of ATN1 is unlikely, given the presence of an (albeit very small) number of healthy individuals with heterozygous stop gain, frameshift and canonical splice variants in databases of healthy individuals and the clustering of the variants in CHEDDA within a specific restricted protein motif.
How do you test for ATN1–neurodevelopmental condition?
The testing can be arranged by a pediatrician or a geneticist and involves a blood or saliva collection. The DNA is tested for changes in the DNA code of the ATN1 gene. The changes identified are de novo, meaning that they are new changes found in affected individuals and neither parent is likely to be a carrier.
How is an ATN1-related neurodevelopmental condition inherited?
Individuals with CHEDDA typically come from families that have no family history of neurodevelopmental disorders or congenital conditions. The ATN1 gene change occurs for the first time in the person with the condition. On occasion, one parent may have the ATN1 mutation (gene change) in some of their egg or sperm cells but not be affected, as no other organ in their body has the mutation. This is called germline mosaicism and means that there is a very small chance that the parent of an affected child may have another affected child. Therefore genetic counselling is strongly recommended.
What are the chances of an individual having a child with CHEDDA?
While it is unlikely that an individual with CHEDDA who is severely affected will partner and have children, a carrier of a ATN1 mutation that does go on to have children will have a 50% chance with each pregnancy of passing on the ATN1 mutation. Children who inherit an ATN1 mutation from their parent will experience a similar level of challenges as their parent; some may even experience difficulties and symptoms not seen in their parent. Genetic counselling is available through the local genetic service when planning a pregnancy and in early pregnancy.