Molecular Boards: Childhood Genetic Disorders

Front 1

Fragile X syndrome

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 1

Fragile X syndrome

1. trinucleotide repeat (CGG), X-linked. protein FMRP, gene: FMR1. >200 repeats in untranslated portion of exon 1 is abnormal. lesion is polymerase slippage and hypermethylation. Premutation = 60-200 repeats
2. MC cause of inherited MR. classic other features: macroorchidism, long faces, big ears. delayed motor development.
3. Southern blot with methylation sensitive and resistant cutters. careful that normal females have methylation- there will be 2 bands. ALso PCR for the CGG region plus capillary electrophoresis. Sensitivity and specificity are 100%.

Front 2

UPD

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 2

UPD

1. aneuploidy- 2 copies from one parent, loss from the other due to meiotic nondisjunction. Maternal means 2 copies from mom.
2. lots, as express all AR on that chromosome, imprinting, or none. Lots of disorders fall into category. Most frequent: Chediak-Higashi syndrome, Spinal muscular atrophy, CF, B-and A-thal, Familial mediterreanian fever, 21- hydroxylase def.
3. testing is typically SNP and comparing parents to child. can be done by PCR, sequencing, restriction digest.

Front 3

Imprinting: prader Willi and Angelman

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 3

Imprinting: prader Willi and Angelman

1. UPD or other method of getting only maternal or paternal copies of chr 15, specifically 15q11-q13. Different genes are expressed here depending on origin due to methylation. MC cause of Prader Willi is a 4 MB deletion in the PATERNAL copy through unequal cross-over (Maternal UPD is 20%). AS is MC caused by deletion of maternal copy as well.
2. PW- MR, hypotonia, obese; AS- MR, gait, speech impairment, microcephaly
3. double-digest Southern, or PCR followed with similar methylation sensitive enzymes. Maternal SNRPN region is methylated, paternal is not.

Front 4

Rett Syndrome

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 4

Rett Syndrome

1. X-linked, affects only females
2. show normal development for 6-18 months, then regress, loss of speech, developmental delay, seizures. MECP2 gene.
3. DNA sequencing of 4 exons.

Front 5

Williams Syndrome

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 5

Williams Syndrome

1. AD, deletion of one copy of the elasin gene on 7q11. Is a contiguous gene deletion syndrome, flanked by LCS or "duplicons".
2. dysmorphic facial features (elfish)? growth delay, CV disease, outgoing personality.
3. FISH.

Front 6

Duchenne muscular dystrophy

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 6

Duchenne muscular dystrophy

1. X-linked, MC x-linked recessive lethal disease. DMD is the largest gene, >2000KB. protein is dystrophin.
2. Progressive weakness and degeneration of skeletal muscle.
3. Most mutations in DMD are deletions. Southern for deletions (65%) or multiplex PCR for multiple common sites of deletion (first choice).

Front 7

Myotonic dystrophy

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 7

Myotonic dystrophy

1. MC inherited muscular dystrophy affecting adults (AD), CTG trinucleotide repeat. premutation is >30, mild effect 50-80, full can be >1000. In the 3' end of the DMPK gene
2. progressive muscle weakness and myotonia in adults.
3. PCR and Southern.

Front 8

Spinal Muscular atrophy

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 8

Spinal Muscular atrophy

1. AR, 2nd MC fatal inherited AR disorder after CF. gene is SMN1 and SMN2., with only 5 bp difference. SMN2 has alt splicing. del of exon 7 is MC cause.
2. severe neuromuscular disease, degeneration of alpha motor neurons in spinal cord, results in proximal weakness/paralysis
3. test is for presence of exon 7, use RG-PCR of exon 7- this adds a restriction site after PCR. 94% detection

Front 9

Phenylketonuria

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 9

Phenylketonuria

1. PAH gene, AR. over 400 mutations described.
2. Inability to convert phenylalanine to tyrosine.
3. Panel of common mutations, detect >50%. direct sequencing detects 94%.

Front 10

Tay Sachs disease

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 10

Tay Sachs disease

1. AR, HEXA gene
2. Deficiency of hexoaminidase A, a lysozomal enzyme, results in accumilation of glycolipid Gm2, which is toxic, multisystem, death by age 4 (after seemingly normal development).
3. AShkanazi and other populations have 10x incidence. PCR followed by ASO (allele specific oligo) hybridization. 80% is a 4 bp insertion in exon 11,

Front 11

Gaucher disease

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 11

Gaucher disease

1. AR lysosomal storage disease. GBA is the gene, 200 mutations identified.
2. defective glucocerebrosidase leased to accumilation of glucoserebroside in the liver, bone marrow, spleen, and lung.
3. 4 mutations responsible for 95% of disease in Ashkanazi 5x carrier rate), and >50% others. There is a pseudogene, so primer selection with PCR must be careful for sequencing.

Front 12

Cystic Fibrosis

1. mutation type/genetics?
2. clinical signs/symptoms?
3. detection methods?

Back 12

Cystic Fibrosis

1. MC lethal AR disease, incidence 1 2500-3300. Gene is CFTR. 1400 mutations id'd, but only really frequent is DF508. this is a 3bp del in exon 10 seen in 70% of patients.
2. viscous mucus 2/2 faulty transport of sodium and chloride. median Dx 6-8 months. Die of pulmonary disease, most have pancreatic insufficiency.
3. core population panel for screening, probe hybridization, multiplexed blot tests, third wave.