Exome sequencing can be used to find disease genes for facialabnormalities, missing fingers/toes, frequent mosaicism, extremely rare disease (approximately 1 case per 1 million newborns)
Can occur by extension of short 'tandem' repeats. Above a certain size, these sequences become unstable. Dynamic mutations in UTR or coding sequences can be associated with disease.
Huntington disease is caused by CAG repeat expansion in the gene HTT, which codes for huntingtin. The mutant huntingtin has an expanded poly-glutamine tract and forms protein aggregates, which do not promote secretion of neurotransmitters and lead to apoptosis.
Occurs when a disease manifests earlier and/or increases severity with successive generations. Anticipation is suspected when a mild disorder is observed in a parent/relative after diagnosis in the child/index patient.
Mutations are mainly recessive. For some genes, product amounts from one copy instead of two are not sufficient, leading to haploinsufficiency. Mutations causing haploinsufficiency are usually dominant.
Can be associated with gross overexpression of certain genes, acquisition of a novel function and production of chimeric genes, modification of cellular signalling responses.
Chronic myeloid leukemia is caused by a translocation between chromosomes 9 and 22 resulting in a fusion gene BCR-ABL1, which encodes a constitutively active tyrosine kinase.
Mutations in genes for connective tissue proteins such as collagens can explain normal protein assembly and disease mechanisms caused by protein misfolding.
Collagen type I consists of two α1-chains and one α2-chain. These chains have to align in order to start the folding process of procollagen type I into a triple helix. After this folding process, post-translational modifications and collagen trimming by specific proteins have to take place.
Osteogenesisimperfecta (OI) can be caused by mutations in COL1A1 and COL1A2 (and several other genes). The severity of the disease depends on the type and position of the mutation.
Genotype/phenotype correlation in Osteogenesis imperfecta
Dominant negative mutations that impair the coordinated assembly of collagen fibers explain the strong genotype/phenotype correlation. Mutations in N-terminal domains lead to milder diseases than mutations inC-terminal domains.