Medical Genetics and Genomics: Chromosomes, Epigenetics, Microdeletions, and Repeat Disorders

Comprehensive vocabulary flashcards covering the human genome, cytogenetics, aneuploidies, microdeletions and duplications, epigenetics, imprinting, and dynamic repeat disorders.

Human Haploid Genome

The complete set of nuclear DNA in a human gamete, comprising $22$ autosomes plus an $X$ or $Y$ chromosome, spanning approximately $3.2\text{ billion base pairs}$.

Alternative RNA Splicing

A regulatory mechanism predicted for $>90\%$ of human genes by which multiple distinct protein isoforms are generated from a single primary transcript, producing roughly $200{,}000$ transcripts from $20{,}000$ protein-coding genes.

Dark Matter (Non-Coding Genome)

The approximately $98.5\%$ of human genomic DNA that does not encode protein sequences, consisting of noncoding RNA genes, regulatory elements, pseudogenes, and repetitive transposons.

Single Nucleotide Polymorphism (SNP)

A single base pair position in genomic DNA where alternate sequence alleles exist among individuals; it represents the most common class of human genetic variation.

Variable Number Tandem Repeat (VNTR)

A minisatellite repetitive element composed of tandem repeats of approximately $10\text{--}60\text{ bp}$ core motifs, highly polymorphic between individuals and widely used in DNA fingerprinting and forensics.

Short Tandem Repeat (STR)

A microsatellite repetitive element composed of tandem repeats of $2\text{--}10\text{ bp}$ motifs, highly abundant across the genome and utilized for genetic mapping and forensic profiling such as the FBI CODIS panel.

Short Interspersed Element (SINE)

A non-autonomous mobile retrotransposon under $500\text{ bp}$ in length, predominantly represented in humans by $Alu$ elements, which make up roughly $12\%$ of the genome with over $1\text{ million}$ copies.

Long Interspersed Element (LINE)

An autonomous mobile retrotransposon over $5{,}000\text{ bp}$ in length; the human $L1$ family encodes reverse transcriptase to mediate its own transposition and comprises approximately $16\%$ of the genome.

Somatic Mosaicism

The occurrence of two or more genetically distinct cell populations within an individual arising from post-zygotic spontaneous mutations, replication errors, or chromosomal alterations.

Malformation

A morphological defect of an organ, part of an organ, or larger region of the body resulting from an intrinsically abnormal developmental genetic program, such as polydactyly or syndactyly.

Deformation

An abnormal form, shape, or position of a body part caused by mechanical extrinsic forces physically impinging on the fetus during development.

Disruption

A morphological defect resulting from the extrinsic breakdown or destruction of previously normal, irreplaceable fetal tissue, such as limb amputations resulting from amnion rupture sequence.

Sequence

A pattern of multiple secondary structural anomalies that cascade downstream from a single primary causative event or localized mechanical insult occurring in development.

Syndrome

A recognizable pattern of multiple congenital anomalies occurring together in parallel that are thought to share a common pathogenic etiology rather than representing a single secondary cascade.

Acrocentric Chromosome

A chromosome structure wherein the centromere is positioned very close to one end, producing very short $p$ arms containing satellite stalks encoding ribosomal RNA; in humans, chromosomes $13$, $14$, $15$, $21$, and $22$.

Robertsonian Translocation

A specialized chromosomal rearrangement caused by fusion of the long ($q$) arms of two acrocentric chromosomes at or near the centromere, accompanied by the loss of their short ($p$) arms.

Meiotic Nondisjunction

The failure of paired homologous chromosomes to segregate during meiosis I or sister chromatids to separate during meiosis II, generating aneuploid gametes with extra or missing chromosomes.

Trisomy 21 (Down Syndrome)

The most frequent viable autosomal aneuploidy ($1\text{ in }850$ live births), presenting with brachycephaly, upslanting palpebral fissures, Brushfield spots, single palmar crease, atrioventricular canal defects, and mild-to-moderate intellectual disability.

Trisomy 18 (Edwards Syndrome)

An autosomal aneuploidy ($1\text{ in }7{,}900$ live births) characterized by small for gestational age status, prominent occiput, clenched hands with overlapping fingers, rocker-bottom feet, ventricular septal defects, and profound intellectual disability.

Trisomy 13 (Patau Syndrome)

An autosomal aneuploidy ($1\text{ in }9{,}500$ live births) characterized by holoprosencephaly, microphthalmia, cutis aplasia, cleft lip/palate, postaxial polydactyly, congenital heart disease, and profound developmental disability.

Turner Syndrome

A sex chromosome aneuploidy ($45,\text{X}$ in $50\%$) occurring in $1\text{ in }2{,}500$ live female births, presenting with short stature, gonadal dysgenesis, webbed neck, broad chest with widely spaced nipples, lymphedema, and aortic coarctation.

Klinefelter Syndrome

A sex chromosome aneuploidy ($47,\text{XXY}$) occurring in $1\text{ in }600$ male births, presenting with tall stature, post-pubertal testosterone deficiency, small testes, gynecomastia, infertility, and low-normal verbal IQ.

Pedigree Symbols

Standardized genealogical conventions representing sex, affected phenotypes, carrier status, proband designation, and assisted reproductive technologies in clinical genetics.

Ancestry Informative Markers (AIMs)

Specific genetic alleles that exhibit substantial differences in allele frequencies among ancestral human populations originating in different geographic regions of the world.

22q11.2 Deletion Syndrome

The most common microdeletion syndrome ($1\text{ in }3{,}000\text{--}4{,}000$), caused primarily by a recurrent de novo $3\text{ Mb}$ deletion involving $TBX1$, presenting with cleft palate, tetralogy of Fallot, tubular nose, hypocalcemia, immunodeficiency, and risk of schizophrenia.

Pierre Robin Sequence

A developmental sequence characterized by primary micrognathia that causes posterior displacement of the tongue (glossoptosis), which physically prevents palatal shelf closure and results in a U-shaped cleft palate.

Nonallelic Homologous Recombination (NAHR)

An aberrant meiotic crossing-over mechanism between flanking homologous low-copy repeats (segmental duplications) that generates reciprocal microdeletions and microduplications.

Chromosomal Microarray (CMA)

A first-line diagnostic technique using dense oligonucleotide or SNP probe arrays to detect submicroscopic copy number variants ($\ge 50\text{ kb}$) across the genome; cannot detect balanced rearrangements.

Variable Expressivity

The clinical phenomenon wherein individuals possessing the exact same pathogenic genetic variant exhibit different manifestations, severities, or affected organ systems.

Incomplete Penetrance

The situation in which a proportion of individuals who inherit a disease-causing genotype do not express any detectable clinical signs or symptoms of the disorder.

16p11.2 Deletion Syndrome

A recurrent $600\text{ kb}$ microdeletion syndrome occurring in $1\text{ in }4{,}000$ individuals, representing a strong risk factor for autism spectrum disorder ($20\%$ affected), speech delays, intellectual disability, and obesity.

Cri du Chat Syndrome

A terminal chromosomal deletion disorder involving $5\text{p}$ ($1\text{ in }15{,}000$ live births), characterized by microcephaly, hypertelorism, severe intellectual disability, and a characteristic high-pitched cat-like cry.

Williams Syndrome

A microdeletion disorder caused by a $1.6\text{ Mb}$ loss at $7\text{q}11.23$ encompassing $ELN$, characterized by supravalvular aortic stenosis, stellate irises, cheerful disposition, initial speech delay followed by strong verbal fluency, and mild intellectual disability.

Quadrivalent Formation

A cross-shaped four-chromosome meiotic pairing configuration formed in carriers of reciprocal translocations, which can segregate via alternate (normal/balanced), adjacent-1 (unbalanced), or adjacent-2 (unbalanced) patterns.

Pericentric Inversion

A structural chromosomal inversion involving two breaks that span across the centromere, creating risk for recombinant chromosomes with duplications and deletions in offspring.

Paracentric Inversion

A structural chromosomal inversion involving two breaks confined entirely within one chromosome arm, which produces dicentric or acentric recombinant gametes that are non-viable, yielding only balanced liveborn offspring.

Epigenetics

Stable, long-term modifications of transcriptional potential and gene activity mediated by chromatin alterations (such as DNA methylation and histone acetylation) that do not alter the underlying nucleotide sequence.

DNA Methylation

The covalent addition of a methyl group to cytosine bases within CpG dinucleotides at CpG islands and shores, leading to chromatin compaction and transcriptional repression.

Histone Acetylation

The enzymatic transfer of acetyl groups onto histone lysine tails by histone acetyltransferases (HATs), neutralizing positive charge to decondense chromatin and activate gene transcription.

XIST (X-Inactive Specific Transcript)

A non-translated long noncoding RNA (lncRNA) that coats the future inactive X chromosome in cis and recruits silencing complexes to mediate dosage compensation via X inactivation.

Evolutionary Conserved Regions (ECRs)

Non-coding genomic sequences shared across divergent species that represent critical, highly conserved cis-regulatory elements such as distal enhancers and silencers.

Homeodomain Proteins

A class of sequence-specific DNA-binding transcription factors encoded by homeobox genes that govern spatial anatomical patterning and phenotypic cell fate during embryonic development.

Antennapedia Mutation

A classic homeotic gain-of-function mutation in Drosophila that alters developmental specification, transforming antennae on the head into fully formed ectopic walking legs.

Fragile X Syndrome (FXS)

The most common inherited intellectual disability, caused by an expansion of $>200$ $CGG$ repeats in the $5'\text{-UTR}$ of $FMR1$, which induces promoter hypermethylation, chromatin silencing, and loss of FMRP protein.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

A late-onset neurodegenerative disorder in $FMR1$ premutation carriers ($55\text{--}200$ $CGG$ repeats), driven by toxic RNA gain-of-function that sequesters nuclear proteins into intranuclear inclusions, causing gait ataxia and tremor.

Repeat-Associated Non-AUG (RAN) Translation

An unconventional translation process across expanded nucleotide repeats in the absence of an AUG start codon, generating toxic homopolymeric peptides that form pathological inclusion bodies.

Genomic Imprinting

An epigenetic modification established during gametogenesis that causes monoallelic gene expression in somatic tissues based strictly on parental origin.

Uniparental Disomy (UPD)

The inheritance of both homologous copies of a chromosome pair from a single parent, which can lead to disease if the chromosome contains imprinted regions or unmasks recessive mutations.

Uniparental Isodisomy

A form of UPD wherein an individual inherits two identical copies of a single parental chromosome homolog, resulting in extensive tracts of homozygosity detectable on SNP microarrays.

Uniparental Heterodisomy

A form of UPD wherein an individual inherits two distinct homologous chromosomes from the same parent, indicating non-disjunction in meiosis I without large tracts of homozygosity.

Prader-Willi Syndrome (PWS)

A genetic condition caused by loss of paternally expressed genes at $15\text{q}11.2\text{-q}13$ ($70\%$ paternal deletion, $25\%$ maternal UPD, $2\%$ imprinting center defect), characterized by severe neonatal hypotonia, failure to thrive, cryptorchidism, and childhood hyperphagia resulting in obesity.

Angelman Syndrome (AS)

A neurodevelopmental disorder caused by loss of maternal $UBE3A$ expression at $15\text{q}11.2\text{-q}13$ ($70\%$ maternal deletion, $11\%$ sequence variant, $5\%$ paternal UPD, $3\%$ IC defect), presenting with ataxic gait with uplifted arms, inappropriate happy laughter, microcephaly, seizures, and absent speech.

MS-MLPA

Methylation-specific multiplex ligation-dependent probe amplification; a molecular method employing methylation-sensitive endonucleases and probe-specific ligation to simultaneously detect copy number variations and differential DNA methylation at imprinted loci.

Beckwith-Wiedemann Syndrome (BWS)

An imprinting overgrowth disorder linked to $11\text{p}15.5$ ($50\%$ IC2 loss of methylation, $20\%$ paternal UPD, $5\%$ IC1 gain of methylation), presenting with macrosomia, macroglossia, abdominal wall defects (omphalocele), hemihyperplasia, and elevated risk of Wilms tumor.

Silver-Russell Syndrome (SRS)

An imprinting undergrowth disorder linked to $11\text{p}15.5$ ($35\text{--}50\%$ IC1 hypomethylation) or maternal UPD7 ($7\text{--}10\%$), presenting with severe intrauterine and postnatal growth restriction, relative macrocephaly, body asymmetry, and a triangular facial appearance.

Huntington Disease (HD)

An autosomal dominant, fully penetrant ($\ge 40$ repeats) neurodegenerative disorder caused by an expanded $CAG$ repeat in the $HTT$ gene, presenting with progressive motor chorea, cognitive deterioration, and psychiatric symptoms.

Anticipation

The clinical phenomenon in dynamic repeat expansion disorders wherein successive generations experience an earlier age of disease onset and increasingly severe symptoms due to intergenerational repeat expansion.

Myotonic Dystrophy Type 1 (DM1)

An autosomal dominant disorder caused by a $CTG$ trinucleotide expansion in the $3'\text{-UTR}$ of $DMPK$, leading to nuclear retention of toxic mutant RNA, progressive muscle weakness, myotonia, cataracts, cardiac conduction defects, and maternal anticipation.

Myotonic Dystrophy Type 2 (DM2)

An autosomal dominant disorder caused by an unstable $CCTG$ tetranucleotide repeat expansion in intron 1 of $CNBP$ ($75\text{--}11{,}000$ repeats), presenting with proximal muscle weakness and cataracts without congenital presentation or clinical anticipation.