2 Genetics and Pediatric Rheumatic Diseases

Question 1

Diseases for which genetic mutations are causative

Answer 1

Monogenic diseases

Question 2

Diseases for which genetic variants influence susceptibility

Answer 2

Genetically complex diseases

Question 3

Disease that are caused by high-impact genetic variants or mutation(s) of a single gene and they are usually transmitted in families in a mendelian fashion

Answer 3

Monogenic diseases

Question 4

Monogenic vs genetically complex: Primary autoinflammatory syndromes

Answer 4

Monogenic

Question 5

Monogenic vs genetically complex: Most pediatric rheumatic diseases

Answer 5

Genetically complex

Question 6

Monogenic vs genetically complex: SLE, JDM, JIA

Answer 6

Genetically complex

Question 7

Produces a ribonucleic acid (RNA) copy of the entire gene, known as the primary transcript

Answer 7

Transcription

Question 8

Process through which the nucleic acid sequence is translated into the amino acid code

Answer 8

Translation

Question 9

The central dogma of molecular biology

Answer 9

The human genome is composed of deoxyribonucleic acid (DNA) that encodes genes; DNA is copied into ribonucleic acid (RNA) transcripts through a process called transcription; RNA transcripts are then processed and spliced; mature or spliced transcripts act as a template for protein synthesis or translation

Question 10

Product of transcription

Answer 10

Primary transcript (RNA)

Question 11

Product of RNA splicing

Answer 11

Mature transcript (mRNA)

Question 12

Product of translation

Answer 12

Protein (amino acids)

Question 13

Segments of exons that precede the initiation codon or follow the termination codon

Answer 13

Untranslated regions (UTRs; segments of exons not translated into protein)

Question 14

UTRs that precede the start codon

Answer 14

5′ UTR or leader sequence

Question 15

UTRs that follow the stop codon

Answer 15

3′ UTR or trailer sequence

Question 16

T/F UTRs are non-essential

Answer 16

F, essential regulatory regions that govern the initiation and termination of translation in a sequence-specific manner

Question 17

T/F More than half of known genes, accounting for almost one-fifth of the genome, do not encode proteins.

Answer 17

T

Question 18

Approximately ___ of the human genome is noncoding DNA

Answer 18

98.5%

Question 19

Segments of noncoding DNA immediately preceding genes that, upon binding by transcription factors and RNA polymerase II, facilitate transcriptional initiation

Answer 19

Promoters

Question 20

Gene regions that can engage with transcription factors and gene promoters to enhance or modify gene expression

Answer 20

Enhancers

Question 21

Project that revealed that more than 80% of the genome has an identifiable regulatory function

Answer 21

ENCODE

Question 22

It has been demonstrated that FMF-causing variants are protective against ___

Answer 22

Certain pathogenic Yersinia species, including Y. pestis

Question 23

The simplest type of genetic variant where one nucleotide base is substituted for another

Answer 23

Single nucleotide polymorphism (SNP) or single nucleotide variation (SNV)

Question 24

Genetic variant type vs genetic variant location: A critical determinant of whether the genetic variant will lead to a functional consequence

Answer 24

Location

Question 25

Types of variants that change the amino acid sequence of proteins

Answer 25

1) Missense variants
2) Nonsense variants
3) Splice-site variants
4) Insertions or deletions (indels)

Question 26

Exonic SNPs that result in the substitution of one amino acid for another in protein products

Answer 26

Missense variants

Question 27

SNPs that lead to the replacement of an amino acid with a stop codon, resulting in the premature termination of protein products

Answer 27

Nonsense variants

Question 28

Indels which add or subtract nucleic acids in multiples of three and retain the mRNA reading frame

Answer 28

In-frame indels

Question 29

Indels in which the nucleotide bases are added or subtracted in quantities that alter the mRNA reading frame after the indel

Answer 29

Frameshift indels

Question 30

Variants that may affect the splice site at or near an intron-exon junction, leading to abnormally spliced mature transcripts

Answer 30

Splice site variants

Question 31

Genetic variants that correlate with the expression level of a gene

Answer 31

Expression quantitative trait loci (eQTLs)

Question 32

The gold standard investigative approach for the study of genetically complex diseases

Answer 32

Genome-wide association studies (GWAS)

Question 33

Used to identify mutations in subjects suspected to have known monogenic diseases, which might include Marfan syndrome, familial osteochondral dysplasia, or one of the monogenic autoinflammatory syndromes

Answer 33

Conventional sequencing

Question 34

A statistical method that identifies segments of the genome that cosegregate with monogenic phenotypes of interest within families

Answer 34

Linkage analysis

Question 35

The probability that a linkage interval contains the causative variant is expressed as a

Answer 35

Logarithm of odds (LOD)

Question 36

LOD score of ____ is considered to be significant, indicating that within the study family or families, the pattern of concordance between the gene segment and the phenotype of interest would occur by random chance at a probability of less than 1 in 10,000

Answer 36

4 or greater

Question 37

Prior to the advent of high-throughput sequencing techniques, ___ was the gold standard approach for the investigation of familial disease

Answer 37

Linkage analysis

Question 38

Statistical method used in the first study to map the FMF gene to the short arm of chromosome 16

Answer 38

Linkage analysis

Question 39

Major limitation of linkage analysis

Answer 39

Requires relatively large families to achieve adequate statistical power to specifically identify a single significant linkage interval

Question 40

Investigational approach that can reveal causative mutations in a single step with the flexibility to evaluate individual subjects, small or large families, groups of unrelated subjects, or combinations thereof

Answer 40

High-Throughput Sequencing-Based Studies

Question 41

Deficiency of adenosine deaminase 2 (DADA2) is one of the most striking immune-mediated diseases to be elucidated by this investigational approach

Answer 41

NGS approach