By Keith S. Wexler, MBA, Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.
Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.
Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center
Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital
Background: There are over 500 conditions that have been implicated in Autism, Intellectual or Developmental Disabilities.
- Routine Chromosome Studies will detect 3-5% of patients with Autism, Developmental Disabilities or Intellectual Disabilities
- Fragile X testing is important especially in males (2-4% of males have Autism, Developmental Disabilities or Intellectual Disabilities 1-2% of females)
- Other X Linked gene mutations
- Rett Syndrome (X Linked in Girls) 0-4.4% – Average 1.5%: MECP2 gene, CDKL5 gene
- Inborn Errors of Metabolism 1-5% cause Autism, Developmental Disabilities or Intellectual Disabilities
- 35% have a copy number variation (CNV’s)
- 40% of CNV’s are new (de novo)
- 14% of these patients have Autism, Developmental Disabilities or Intellectual Disabilities
- 10% clear association with Autism, Developmental Disabilities or Intellectual Disabilities
14 major regions identified and correlated with Autism, Developmental Disabilities or Intellectual Disabilities.
Brain (Neuroimaging) 6-48% depending on severity of condition.
Other Causes: Prematurity, Spina Bifida, Cerebral Palsy, Infection.
If Chromosomal Microarray detects an unusual variant which is considered significant (up to 45 known at present):
- Approximately 20 are associated with heart problems
- Approximately 14 are associated with vision or hearing problems
- Approximately 6 are associated with seizures
- Approximately 5 are associated with kidney problems
- Approximately 2 are associated with blood disorders
What are the differences between?
- Metabolic tests – Amino or Organic Acidurias
- Chromosome karyotype tests
- Chromosomal microarray testing
- Next generation sequencing (NGS)
What is the difference between chromosomal testing and exome testing?
- The exome includes the protein coding genes
- There are 23 pairs of chromosomes, 22 pairs of autosomes and 2 sex chromosomes. 2X’s in a normal female (usual female) and 1X and 1Y in a normal male (usual male)
Blood Leukocyte Karyotyping: Culture of circulating WBC’s in the blood of an individual, stopping the growth of the cells when they are dividing, exploding the cells and staining and matching the individual chromosomes.
Examining the number, integrity and intactness of each chromosome, looking for an increased or decreased number and the gain or loss or exchange of chromosomal material. There are 22 pairs of autosomes, 1 from each parent, 2X chromosomes in the usual female and 1X and 1Y chromosome in the usual male.
*Chromosomal Microarray: Is evaluation of the components of the individual chromosomes, evaluating small additions or deletions of chromosomal material not identified by microscopic evaluation of chromosomes. Variations in the number of copies of DNA within a sequence are common and gains or losses may be associated with a disorder or increased or decreased susceptibility to a disorder e.g. CGG repeats in Fragile X. *First test considered for Autism, Developmental Disabilities or Intellectual Disabilities
Next Generation Sequencing (NGS): or High Throughput Sequencing: Term used to described several different types of sequencing DNA or RNA segments more quickly and economically. At the present time, is generally considered “experimental” in an individual.
What is the Exome? The protein forming genes in an individual.
What is the Genome? Complete set of genes or genetic material in an individual.