lect 22 n 23 Chromosome Microarray Analysis (CMA) and Copy Number Variants (CNVs)

Flashcards covering vocabulary and key concepts from Chromosome Microarray Analysis (CMA) and Copy Number Variant (CNV) identification as presented in the lecture.

Chromosome Microarray Analysis (CMA)

A technique used for the detection of copy number variants (CNVs) and regions of homozygosity, providing approximately $1000 \times$ greater resolution than traditional karyotyping.

Copy Number Variants (CNVs)

DNA structural variations involving the gain (duplication) or loss (deletion) of genomic segments, generally ranging from $50\text{ bp}$ to $3\text{ Mb}$ in size.

Balanced Structural Variation (SV)

Structural changes in the genome that do not result in a loss or gain of genetic material, such as inversions and translocations.

Unbalanced Structural Variation (SV)

Structural changes that involve the loss or gain of genetic material, represented by deletions, insertions, tandem duplications, and interspersed duplications.

Haploinsufficiency

A molecular mechanism where a single functional copy of a gene is not enough to maintain a normal phenotype.

Triplosensitivity

A molecular mechanism where the presence of an extra copy of a dosage-sensitive gene results in a disease phenotype.

Log R Ratio (LRR)

A normalized measure of total signal intensity for a SNP; deviations from $0$ provide evidence for copy number changes like deletions or duplications.

B Allele Frequency (BAF)

A normalized measure of the allelic intensity ratio of two alleles ($A$ and $B$), used to identify copy number changes, mosaicism, or uniparental disomy.

SNP Array

A type of microarray that identifies genomic gains and losses, copy neutral aberrations, and regions of homozygosity (ROH) without requiring a normal reference control DNA.

Array CGH (Comparative Genomic Hybridization)

A microarray platform where patient genomic DNA is compared directly to a normal reference control DNA to detect genomic gains and losses.

Regions of Homozygosity (ROH)

Large stretches of the genome where both alleles are identical, which can indicate identity by descent, consanguinity, or uniparental disomy.

Uniparental Disomy (UPD)

The inheritance of two homologous chromosomes from a single parent, rather than one from each parent.

Isodisomy

A form of UPD where the individual inherits two copies of the same parental homologue; this is detectable by microarray as a large region of homozygosity.

Heterodisomy

A form of UPD where the individual inherits two different homologues from the same parent; this is generally not detected by SNP microarray analysis.

Trisomy Rescue

A meiotic mechanism where a trisomic zygote loses one of the extra chromosomes, which can result in uniparental disomy if the two remaining chromosomes are from the same parent.

Angelman Syndrome (AS)

A neurodevelopmental disorder typically caused by a maternal deletion of $15q11q13$ or paternal UPD $15$, characterized by severe intellectual disability and a happy demeanor.

Prader-Willi Syndrome (PWS)

A disorder typically caused by a paternal deletion of $15q11q13$ or maternal UPD $15$, characterized by hypotonia, feeding difficulties in infancy, and later obesity.

Kagami-Ogata Syndrome (KOS)

A syndrome associated with paternal UPD $14$, characterized by dysmorphic features, abdominal wall defects, and a bell-shaped thorax with "coat hanger ribs."

22q11.2 Deletion Syndrome

Also known as DiGeorge or Velocardiofacial syndrome; it is the most frequent contiguous gene deletion syndrome, often caused by non-allelic homologous recombination (NAHR) between low copy repeats.

Charcot Marie Tooth Type 1A (CMT1A)

A peripheral neuropathy caused by a $1.3\text{ Mb}$ duplication of the $PMP22$ gene on chromosome $17p12$.

Hereditary neuropathy with liability to pressure palsies (HNPP)

A mild peripheral neuropathy caused by the deletion of the $PMP22$ gene.

Mosaicism

The presence of two or more cell lineages with different genotypes in a single individual, arising from a single zygote.

Non-Allelic Homologous Recombination (NAHR)

A mechanism where low copy repeat (LCR) sequences cause DNA to misalign during meiosis or mitosis, resulting in recurrent deletions or duplications.

Reporting Thresholds for CNVs

The current standard size thresholds for reporting are deletions $> 200\text{ Kb}$ and duplications $> 500\text{ Kb}$, unless located within a clinically relevant gene.

Long-Read Sequencing (LRS)

An emerging technology that produces reads $> 100\text{ Kb}$ (potentially up to $4\text{ Mb}$), capable of spanning complex structural variants and potentially replacing other genetic tests.