Dit document omvat mijn samenvatting (info slides + notities) van Les 7 van het vak Neurogenetics gegeven door Rosa Rademakers. Ik heb dit voor elke les, buiten les 10. Daarvan heb ik wel notities bij de slides. Je mag me hiervoor ook altijd contacteren :))
Class 7: genetics of Neurocutaneous
syndromes
Genetic mechanisms of heterozygous pathogenic
variants
- The genes implicated in Noonan syndrome and Noonan syndrome with
multiple lentigines are all part of the RAS-pathway and result mostly
from dominant activating variants causing increased signalling through
the RAS-MAPK pathway.
- A: homozyogous wild type allele in specific gene in all somatic
nucleated cells
- B: heterozygous pathogenic variant in specific gene in all somatic
nucleated cells
- Examples of cases of Noonan syndrome
o Most of the children have drooping eye lids
o Wide spead eyes
o Webbed neck
o …
- Many of the syndromes are caused by a heterozygous pathogenic variant in a
tumour suppressor gene with subsequent somatic inactivation of the normal
allele in aKected tissue
- PRKAR1A, NF1, SPRED1, NF2, SMARCB1, LZTR1, PTCH1, SUFU, PTEN, TSC1,
TSC2, VHL
- Autosomal dominant inheritance pattern but need for biallelic inactivation to
cause symptoms (recessive at the cellular level)
- A large intrafamilial variability in phenotypic expression is often seen because of
interindividual variability in the number, timing and location of second hits in wt
allele.
- The severity of the phenotype is often diKicult to predict from the genotype
- When you lose the other allele in the cell the cell starts to grow. Most of the
syndromes caused by a heterozygous pathogenic variant in the TSG are inherited
in an autosomal dominant way but if you look at the abnormal tissue you see a
second hit
o Whole list of conditions this occurs
- Each cell division have the risk of introducing a pathogenic variant
o in normal allele -> clump of cell that have both alleles inactivated
Café-au-lait spots
- Focal hyperpigmentation
- Always darker than surrounding skin
- Melanocytes with second hit in the NF1 gene
o Second hit is independent
- The size of the spot is correlated when the mutation occurs
- It shows that mutations are not rare, mutations in diving cells happen all the time
, TSC: clinical characteristics
- Little tumors at the level of the skin
- Other lesions at the level of the brain
o Second hit responsible for lesions
Nevoid basal cell carcinoma syndrome (NBCC)
- Basal cell carcinoma
o Usually don’t metastase
- Each of the tumors have a second hit
- A number of children develop a brain tumor
o Once they become older they disappear
Mosaicism
X-linked
- Epigenetic mosaicism due to inactivated x-chromosome
- The pathogenic variants in genes involved in the X-linked dominant
inherited syndromes are typically seen in females and are
embryonically lethal in males (IKBKG, NSDHL, HCCS, COX7B,
NDUFB11,OFD1)
- In a typical female with 2 X-chromosomes there is a patchwork with
cells where one X is inactivated
- There are females with 3 X chromosomes and then 2 are inactivated
- There are certain conditions know on the chromosome that are X-linked
dominant -> always expressed in females in a heterozygous situation
but at the same time are lethal in males
- Patchwork with normal X activated, and regions where the abnormal gene is
inactivated
- In a typical male there is only one X chromosome -> if the gene is present on that
X chromosome = lethal. There are a few exceptions
o Male embryos with Klinefelter syndrome (47,XXY)
o Embryos with a 46,XX male karyotype
o Embryos with post-zygotic mosaicism for the pathogenic variant
o A hypomorphic pathogenic variant associated with minimal activity of the
aKected protein suKicient for the cells to survive
- Example is Incontinentia Pigmenti
o Pathogenic variant in IKBKG (NF-KAPPA-B ESSENTIAL MODULATOR;
NEMO)
o Skin lesions in babies that disappear and leave only pigmentation marks
o Involvement of teeth, eyes and brain (epilepsy and intellectual disability)
o Hypomorphic allele in males cause immune deficiency syndrome
o In female half of the cell of the bone marrow contain a stemcell with the
functioning gene -> provide suKicient white blood cells -> avoid immune
deficiency syndrome
o Linear lesion -> region where the X-chromosome with the mutated gene is
active. They heal out -> after a couple of weeks you see scars
(hyperpigmented in the beginning but after a while with striped)
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