Issue 9/2015. This issue of the publications of the week is about novel genetic findings for neurological disorders that we usually don’t discuss on our blog. Given that there were several reports this week, I thought that thinking a bit outside the box would be a good theme for this week. Follow us on a brief journey of novel genes for Alzheimer’s disease, essential tremor, and agenesis of corpus callosum.
Alzheimer’s disease. The genetics of Alzheimer’s disease are usually not really amenable to the types of studies that we use to find genes for epileptic encephalopathies. In a recent publication in Molecular Psychiatry, Rovelet-Lecrux and collaborators were able to perform trio analysis in 14 patients with early onset Alzheimer’s disease, performing array CGH and sequencing exomes in patients and their parents. The yield of their study is impressive: they found two likely pathogenic de novo copy number variants including an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion. Both genes are key players in the pathogenesis in Alzheimer’s disease. In addition, they found de novo mutations in PSEN1, VPS35 and MARK4. These genes have a known connection to Alzheimer’s disease.
Comments IH. The de novo paradigm extends beyond neurodevelopmental diseases and may even be applicable to late onset neurodegenerative disorders such as dementias. This study is unique as there are usually few possibilities to include parental DNA for testing.
Essential tremor. Essential tremor (ET) is a common neurological condition that results in rhythmic shaking, often of the hands when patients try to perform simple tasks such as holding a glass of water or drinking. Even though tremor can be part of many neurological diseases, essential tremor is a distinct entity – and not well understood from a genetic perspective. In a recent publication in Human Molecular Genetics, Hor and collaborators identify rare variants in TENM4 in three smaller families with ET that segregate with the phenotype. TENM4 encodes teneurin transmembrane protein 4, a neuronal cell adhesion protein, which binds to latrophilin, the target of the black widow spider venom.
Comments IH. For conditions with a completely unknown genetic architecture, smaller family studies that do not satisfy the criteria of genome-wide linkage may be helpful in pointing out candidate genes. However, it should also be kept in mind that these findings may be false positive.
Agenesis of corpus callosum. The corpus callosum is the fiber track that connects both cerebral hemispheres. It is a brain structure that is particularly vulnerable in brain development. If the corpus callosum has not developed at all, this is referred to as agenesis of corpus callosum (ACC), which is a finding in many complex genetic syndromes. However, there are also patients who have ACC, but no other neurological or syndromic features. In a family with isolated ACC published in the European Journal of Human Genetics, Jouan and collaborators identify a compound heterozygous mutation in CDK5RAP2. This gene is also known as MCPH3 and was previously reported to cause autosomal recessive microcephaly.
Comments IH. It is an interesting twist in neurogenetics to see a gene for microcephaly emerge in an entirely unrelated disorder of brain development. This finding suggests that CDK5RAP2 might be a gene with a phenotypic spectrum that needs to be explored.