Genetics

Topics: Chromosome, Genetic disorders, Syndromes Pages: 7 (1148 words) Published: August 28, 2014
Micro-deletion syndromes
Di- George syndrome
Aetiology
Deletion of part of the long arm in chromosome 22 at location 22q11.2(1) The most common deletion includes the  TBX1 gene (85% individuals), see figure 1 below. Defect in neural-crest tissue (thyroid, thymus, and conotruncal septum of the heart) due deletion of region in chromosome 22 (2) Inheritance pattern is autosomal dominant (2)

Hypoplasia of thymus and parathyroid glands resulting in hypocalcemia Acronym CATCH22 is used for this syndrome (Cardiac Abnormality/abnormal facies, T cell deficit due to thymic hypoplasia, Cleft palate, Hypocalcemia ) (2)  a variation in the phenotype and deletion can be in both maternal or paternal origin (1)

Figure 1: shows the genetic map of chromosomal region 22q11.2, 85% individuals have a large 3-Mb deletion (40 genes) (3).

Clinical features (1)
Cardiac malformations (aortic arch anomalies)
Dysmorphic facial features (low set ears , upward and downward slanting eyes, small mouth) (2) Recurrent infections
Neonatal hypocalcaemia – tetany /Seizures
Investigations (3)
Chest Radiography – thymus
FISH (fluorescent in situ hybridisation) the probes TUPLE1 and N25 are used for breakpoints in the region Incidence (4)
1 in 4000 of population (international)

References
1) Connor, J. and Ferguson-Smith, M. (1997). Essential medical genetics. 1st ed. Oxford [England]: Blackwell Science. 2) Omim.org, (2014). OMIM Entry - # 188400 - DIGEORGE SYNDROME; DGS. [online] Available at: http://www.omim.org/entry/188400?search=DI-GEORGE&highlight=digeorge [Accessed 2 Jun. 2014]. 3) Roberta A Pagon, E. (2014). 22q11.2 Deletion Syndrome - GeneReviews® - NCBI Bookshelf. [online] Ncbi.nlm.nih.gov. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1523/ [Accessed 2 Jun. 2014]. 4) Emedicine.medscape.com, (2014). Medscape: Medscape Access. [online] Available at: http://emedicine.medscape.com/article/886526-overview#a0156 [Accessed 2 Jun. 2014]. Prader Willi syndrome (PWS)

Aetiology (1)
75% show a microdeletion at 15q11-q13, and remaining 25% shows maternal uniparental disomy ( lack of paternal genes) Deletion is mostly paternal in origin
Loss of function of genes in this region, maternal genes are inactive There are two types of deletions- “Type 1 deletions (T1D) extend from BP1 to BP3 and type 2 deletions (T2D) extend from BP2 to BP3”, see Figure 1 below (3).

Figure 2: shows genetic and expression map of chromosomal region 15q11.2-q13 (3)

Clinical features (3)
Hypotonia, (late childhood this improves)
Poor-swallowing
Flat face, tented upper lip, prominent forehead
Hypoplastic external genitalia
Palpebral fissures are almond shaped
Small feet and hands
Low mental IQ (20-80)
Incidence (3)
1 in 10, 000 live births
Reoccurrence risks (3)
2% reoccurrence risk due parental structural arrangement

Investigations (2)
CFISH analysis with the SNRPN probe
chromosomal microarrays, identify size of deletion

Reference:

1. Omim.org, (2014). OMIM Entry - # 176270 - PRADER-WILLI SYNDROME; PWS. [online] Available at: http://www.omim.org/entry/176270?search=prader%20williams&highlight=william%20prader [Accessed 2 Jun. 2014]. 2. Roberta A Pagon, S. (2014). Prader-Willi Syndrome - GeneReviews® - NCBI Bookshelf. [online] Ncbi.nlm.nih.gov. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1330/ [Accessed 2 Jun. 2014]. 3. Connor, J. and Ferguson-Smith, M. (1997). Essential medical genetics. 1st ed. Oxford [England]: Blackwell Science. Angelman syndrome (Happy puppet syndrome)

Aetiology (1)
75% show microdeletion at 15q12
Deleted region is mostly maternal in origin
5% shows paternal uniparental disomy
Remaining 20% show unknown molecular pathology

Background (2)

Newborns do not show phenotype
Onset of early development delay around 6 months
Clinical features (3)
Development delay
Poor speech
Jerky movements
Paroxysms of inappropriate laughters
Dysmorphic facial features...
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