GENETIC DISEASES

DR KWAGHE BARKA VANDI (MBBS, FMCPath)

ANATOMIC PATHOLOGIST

GENETIC DISEASES

OUTLINE

• 1. HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

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• 2. CHROMOSOMAL DISORDERS

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• 3. MENDELIAN DISORDERS

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GENETIC DISEASES

OUTLINE

• 4. COMPLEX MULTIGENIC DISORDERS

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• 5. SINGLE GENE DISORDERS WITH NON- CLASSICAL INHERITANCE

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• 6. MOLECULAR DIAGNOSIS OF GENETIC DISEASES

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

• GENE IS THE BASIC UNIT OF INHERITANCE

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• IT IS A DISCRETE LOCUS OF HERITABLE, GENOMIC SEQUENCE WHICH AFFECTS AN ORGANISM'S TRAITS BY BEING EXPRESSED AS A FUNCTIONAL PRODUCT OR BY REGULATION OF GENE EXPRESSION

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• GENOME IS THE COMPLETE SET OF GENES OR GENETIC MATERIAL IN THE CELL OF AN ORGANISM

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

• THE HUMAN GENOME CONTAINS ROUGHLY 3.2 BILLION DNA BASE PAIRS

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• 98.5% OF THE HUMAN GENOME DOES NOT ENCODE PROTEINS

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• ONLY 1.5% (20,000 GENES) OF THE GENOME ENCODE PROTEINS

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

• THESE ENCODED PROTEINS VARIOUSLY FUNCTION AS

• 1. ENZYMES

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• 2. STRUCTURAL COMPONENTS

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• 3.SIGNALING MOLECULES

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• USED TO ASSEMBLE AND MAINTAIN ALL THE CELLS IN THE BODY

HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

• PROTEIN-CODING GENES IN HIGHER ORGANISMS ARE SEPARATED BY LONG STRETCHES OF DNA THAT DO NOT CODE FOR ANY PROTEIN

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• 80% OF THE NONCODING REGIONS OF THE GENOME PROVIDE THE CRITICAL “ARCHITECTURAL PLANNING”

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• PROTEIN ENCODING GENES PROVIDE THE BUILDING BLOCKS AND THE MACHINERY REQUIRED FOR ASSEMBLING CELLS, TISSUES AND ORGANISMS

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

• THE DIFFERENCE BETWEEN WORMS AND HUMANS APPARENTLY LIES MORE IN THE GENOMIC “BLUEPRINTS” THAN IN THE CONSTRUCTION MATERIALS

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• THE MAJOR CLASSES OF FUNCTIONAL NON–PROTEIN-CODING SEQUENCES FOUND IN THE HUMAN GENOME ARE

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1. PROMOTER AND ENHANCER REGIONS PROVIDE BINDING SITES FOR TRANSCRIPTION FACTORS

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

• 2. NONCODING REGULATORY RNA’S. (MORE THAN 60% OF THE GENOME IS TRANSCRIBED INTO RNA’S THAT ARE NEVER TRANSLATED INTO PROTEIN, BUT REGULATE GENE EXPRESSION THROUGH A VARIETY OF MECHANISMS)

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• THE TWO BEST-STUDIED VARIETIES ARE
• (1). MICRO-RNAS (miRNA’S)
• (2). LONG NONCODING RNAS(lncRNA’S)

HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

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• 3. “JUMPING GENES” OR MOBILE GENETIC ELEMENTS (E.G. TRANSPOSONS)

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• MORE THAN ONE THIRD OF THE HUMAN GENOME IS COMPOSED OF THESE ELEMENTS

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• THEY CAN MOVE AROUND THE GENOME FROM POINT TO ANOTHER

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

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• THEY ARE IMPLICATED IN GENE REGULATION AND CHROMATIN ORGANIZATION, BUT THEIR FUNCTION IS STILL NOT WELL ESTABLISHED

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• 4. SPECIAL STRUCTURAL REGIONS OF DNA, IN PARTICULAR TELOMERES (CHROMOSOME ENDS) AND CENTROMERES (CHROMOSOME “TETHERS”)

HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

EPIGENETIC FACTORS

• EVEN THOUGH VIRTUALLY ALL CELLS IN THE BODY CONTAIN THE SAME GENETIC MATERIAL, TERMINALLY DIFFERENTIATED CELLS HAVE DISTINCT STRUCTURES AND FUNCTIONS

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

• EPIGENETICS IS DEFINED AS THE STUDY OF HERITABLE CHEMICAL MODIFICATION OF DNA OR CHROMATIN THAT DOES NOT ALTER THE DNA SEQUENCE ITSELF

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• DIFFERENT CELL TYPES ARE DISTINGUISHED BY LINEAGE-SPECIFIC PROGRAMS OF GENE EXPRESSION

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

• SUCH CELL TYPE-SPECIFIC DIFFERENCES IN DNA TRANSCRIPTION AND TRANSLATION DEPEND ON EPIGENETIC FACTORS

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• LITERALLY, FACTORS THAT ARE “ABOVE GENETICS” THAT CAN BE CONCEPTUALIZED AS FOLLOWS

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• DNA IN CELLS ARE NOT UNIFORMLY OR COMPACTLY WOUND

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

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• NUCLEOSOMES CONSIST OF DNA SEGMENTS 147 BASE PAIRS LONG THAT ARE WRAPPED AROUND A CENTRAL CORE STRUCTURE OF HIGHLY CONSERVED LOW MOLECULAR WEIGHT PROTEINS CALLED HISTONES

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• THE RESULTING DNA-HISTONE COMPLEX RESEMBLES A SERIES OF BEADS JOINED BY SHORT DNA LINKERS AND IS GENERICALLY CALLED CHROMATIN

HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

• AT THE LIGHT MICROSCOPIC LEVEL, NUCLEAR CHROMATIN EXISTS IN TWO BASIC FORMS:

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• (1) CYTOCHEMICALLY DENSE AND TRANSCRIPTIONALLY INACTIVE HETEROCHROMATIN

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• (2) CYTOCHEMICALLY DISPERSED AND TRANSCRIPTIONALLY ACTIVE EUCHROMATIN

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HUMAN GENETIC ARCHITECTURE, GENES & HUMAN DISEASES

GENETIC DISORDERS

• HUMAN GENETIC DISORDERS CAN BE BROADLY CLASSIFIED INTO THREE CATEGORIES:

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• 1. CHROMOSOMAL DISORDERS

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• 2. DISORDERS RELATED TO MUTATIONS IN SINGLE GENES WITH LARGE EFFECTS

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• 3. COMPLEX MULTIGENIC DISORDERS

GENETIC DISORDERS

MUTATIONS

• MUTATION IS DEFINED AS A PERMANENT CHANGE IN DNA

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• MUTATIONS THAT AFFECT GERM CELLS ARE TRANSMITTED TO THE PROGENY AND CAN GIVE RISE TO INHERITED DISEASES

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• MUTATIONS THAT ARISE IN SOMATIC CELLS UNDERSTANDABLY DO CAUSE CANCERS AND SOME CONGENITAL MALFORMATIONS

GENETIC DISORDERS

TYPES OF MUTATIONS

• SOMATIC MUTATIONS
• GERM LINE MUTATIONS

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• SUBSTITUTION
• INSERTION OR DELETION
• FRAME SHIFT
• TRINUCLEOTIDE REPEAT

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GENETIC DISORDERS

POINT MUTATIONS

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• 1. MISSENSE

CONSERVATIVE

NON CONSERVATIVE

• 2. NONSENSE

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CHROMOSOMAL DISODERS

• CHROMOSOMAL DISORDERS ARE ALSO KNOWN AS CYTOGENIC DISORDERS

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• THEY MAY TAKE THE FORM OF AN ABNORMAL NUMBER OF CHROMOSOMES OR AN ALTERATIONS IN THE STRUCTURE OF ONE OR MORE CHROMOSOMES

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• THE NORMAL HUMAN CHROMOSOME COMPLEMENT IS EXPRESSED AS 46,XX FOR THE FEMALE AND 46,XY FOR THE MALE

CHROMOSOMAL DISODERS

• ANY EXACT MULTIPLE OF THE HAPLOID NUMBER OF CHROMOSOMES (23) IS CALLED EUPLOID

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• ANEUPLOIDY OCCURS IF DURING MEIOSIS OR MITOSIS A CELL ACQUIRES A CHROMOSOME COMPLEMENT THAT IS NOT AN EXACT MULTIPLE OF 23

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• THE USUAL CAUSES FOR ANEUPLOIDY ARE NONDISJUNCTION AND ANAPHASE LAG

CHROMOSOMAL DISODERS

• WHEN NONDISJUNCTION OCCURS DURING GAMETOGENESIS, THE GAMETES FORMED HAVE EITHER AN EXTRA CHROMOSOME (N + 1) OR ONE LESS CHROMOSOME (N − 1)

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• FERTILIZATION OF SUCH GAMETES BY NORMAL GAMETES RESULTS IN TWO TYPES OF ZYGOTES—TRISOMIC (2N + 1) OR MONOSOMIC (2N − 1)

CHROMOSOMAL DISODERS

• MONOSOMY OR TRISOMY INVOLVING THE SEX CHROMOSOMES, OR EVEN MORE BIZARRE ABERRATIONS ARE COMPATIBLE WITH LIFE

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• MONOSOMY INVOLVING AN AUTOSOME GENERALLY CAUSES LOSS OF TOO MUCH GENETIC INFORMATION TO PERMIT LIVE BIRTH OR EVEN EMBRYOGENESIS

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• SEVERAL AUTOSOMAL TRISOMIES DO PERMIT SURVIVAL

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CHROMOSOMAL DISODERS

• WITH THE EXCEPTION OF TRISOMY 21, ALL YIELD SEVERELY HANDICAPPED INFANTS WHO ALMOST INVARIABLY DIE AT AN EARLY AGE

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• MITOTIC ERRORS IN EARLY DEVELOPMENT GIVE RISE TO TWO OR MORE POPULATIONS OF CELLS WITH DIFFERENT CHROMOSOMAL COMPLEMENT IN THE SAME INDIVIDUAL

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• A CONDITION REFERRED TO AS MOSAICISM

CHROMOSOMAL DISODERS

• MOSAICISM AFFECTING THE SEX CHROMOSOMES IS RELATIVELY COMMON

CHROMOSOMAL DISORDERS INVOLVING AUTOSOMES

1. DOWN SYNDROME (TRISOMY 21)

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• DOWN SYNDROME IS THE MOST COMMON CHROMOSOMAL DISORDER AND IS A MAJOR CAUSE OF MENTAL RETARDATION

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• 95% OF AFFECTED INDIVIDUALS HAVE TRISOMY 21

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CHROMOSOMAL DISORDERS INVOLVING AUTOSOMES

• FISH WITH CHROMOSOME 21–SPECIFIC PROBES REVEALS THE EXTRA COPY OF CHROMOSOME 21 IN SUCH CASES

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• MOST OTHERS HAVE NORMAL CHROMOSOME NUMBERS, BUT THE EXTRA CHROMOSOMAL MATERIAL IS PRESENT AS A TRANSLOCATION

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CHROMOSOMAL DISORDERS INVOLVING AUTOSOMES

• THE MOST COMMON CAUSE OF TRISOMY AND THEREFORE OF DOWN SYNDROME IS MEIOTIC NONDISJUNCTION

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• THE PARENTS OF SUCH CHILDREN HAVE A NORMAL KARYOTYPE AND ARE NORMAL IN ALL RESPECTS

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• MATERNAL AGE HAS A STRONG INFLUENCE ON ITS INCIDENCE

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CHROMOSOMAL DISORDERS INVOLVING AUTOSOMES

• IN ABOUT 4% OF CASES OF DOWN SYNDROME

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• EXTRA CHROMOSOMAL MATERIAL DERIVES FROM THE PRESENCE OF A ROBERTSONIAN TRANSLOCATION OF THE LONG ARM OF CHROMOSOME 21

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• TO ANOTHER ACROCENTRIC CHROMOSOME (E.G., 22 OR 14)

CHROMOSOMAL DISORDERS INVOLVING AUTOSOMES

• APPROXIMATELY 1% OF DOWN SYNDROME PATIENTS ARE MOSAICS, HAVING A MIXTURE OF CELLS WITH 46 OR 47 CHROMOSOMES

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• THIS MOSAICISM RESULTS FROM MITOTIC NONDISJUNCTION OF CHROMOSOME 21 DURING AN EARLY STAGE OF EMBRYOGENESIS

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CHROMOSOMAL DISORDERS INVOLVING AUTOSOMES

• SYMPTOMS IN SUCH CASES ARE VARIABLE AND MILDER, DEPENDING ON THE PROPORTION OF ABNORMAL CELLS

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• CLEARLY, IN CASES OF TRANSLOCATION OR MOSAIC DOWN SYNDROME, MATERNAL AGE IS OF NO IMPORTANCE

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CHROMOSOMAL DISORDERS INVOLVING AUTOSOMES

• DOWN SYNDROME IS A LEADING CAUSE OF SEVERE MENTAL RETARDATION

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• APPROXIMATELY 80% OF THOSE AFFLICTED HAVE AN IQ OF 25 TO 50

CHROMOSOMAL DISORDERS INVOLVING AUTOSOMES

OTHER TRISOMIES

• A VARIETY OF OTHER TRISOMIES INVOLVING CHROMOSOMES 8, 9, 13, 18, AND 22 HAVE BEEN DESCRIBED

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• TRISOMY 18 (EDWARDS SYNDROME) AND TRISOMY 13 (PATAU SYNDROME)

CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

• GENETIC DISEASES ASSOCIATED WITH CHANGES INVOLVING THE SEX CHROMOSOMES ARE FAR MORE COMMON THAN THOSE RELATED TO AUTOSOMAL ABERRATIONS

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• FURTHERMORE, IMBALANCES (EXCESS OR LOSS) OF SEX CHROMOSOMES ARE MUCH BETTER TOLERATED THAN ARE SIMILAR IMBALANCES OF AUTOSOMES

CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

• SEX CHROMOSOME DISORDERS CAUSE SUBTLE, CHRONIC PROBLEMS RELATING TO SEXUAL DEVELOPMENT AND FERTILITY

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• SEX CHROMOSOME DISORDERS ARE OFTEN DIFFICULT TO DIAGNOSE AT BIRTH

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• MANY ARE FIRST RECOGNIZED AT THE TIME OF PUBERTY

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CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

• THE GREATER THE NUMBER OF X CHROMOSOMES, IN BOTH MALE AND FEMALE, THE GREATER THE LIKELIHOOD OF MENTAL RETARDATION

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• REGARDLESS OF THE NUMBER OF X CHROMOSOMES, THE PRESENCE OF A SINGLE Y DETERMINES THE MALE SEX

CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

1. KLINEFELTER SYNDROME

• BEST DEFINED AS MALE HYPOGONADISM THAT OCCURS WHEN THERE ARE TWO OR MORE X CHROMOSOMES AND ONE OR MORE Y CHROMOSOMES

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• THE INCIDENCE OF THIS CONDITION IS APPROXIMATELY 1 IN 660 LIVE MALE BIRTHS

CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

• THEY HAVE EUNUCHOID BODY HABITUS WITH ABNORMALLY LONG LEGS

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• SMALL ATROPHIC TESTES OFTEN ASSOCIATED WITH A SMALL PENIS

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• LACK SECONDARY MALE CHARACTERISTICS SUCH AS DEEP VOICE, BEARD AND MALE DISTRIBUTION OF PUBIC HAIR

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CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

• THE CLASSIC PATTERN OF KLINEFELTER SYNDROME IS ASSOCIATED WITH A 47,XXY KARYOTYPE (90% OF CASES)

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• 15% OF PATIENTS WITH KLINEFELTER SYNDROME HAVE A VARIETY OF MOSAIC PATTERNS, MOST OF THEM BEING 46,XY/47,XXY

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• OTHER PATTERNS ARE 47,XXY/48,XXXY

CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

• GYNECOMASTIA MAY BE PRESENT

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• THE MEAN IQ IS SOMEWHAT LOWER THAN NORMAL, BUT MENTAL RETARDATION IS UNCOMMON

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• IMPORTANT GENETIC CAUSE OF REDUCED SPERMATOGENESIS AND MALE INFERTILITY

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CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

2. TURNER SYNDROME

• TURNER SYNDROME RESULTS FROM COMPLETE OR PARTIAL MONOSOMY OF THE X CHROMOSOME AND IS CHARACTERIZED BY HYPOGONADISM IN PHENOTYPIC FEMALES

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• IT IS THE MOST COMMON SEX CHROMOSOME ABNORMALITY IN FEMALE

CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

• TURNER SYNDROME IS THE SINGLE MOST IMPORTANT CAUSE OF PRIMARY AMENORRHEA

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• IN TURNER SYNDROME, FETAL OVARIES DEVELOP NORMALLY EARLY IN EMBRYOGENESIS

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• BUT THE ABSENCE OF THE SECOND X CHROMOSOME LEADS TO AN ACCELERATED LOSS OF OOCYTES, WHICH IS COMPLETE BY AGE 2 YEARS

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CHROMOSOMAL DISORDERS INVOLVING�SEX CHROMOSOMES

• “MENOPAUSE OCCURS BEFORE MENARCHE,”

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• THE OVARIES ARE REDUCED TO ATROPHIC FIBROUS STRANDS, DEVOID OF OVA AND FOLLICLES (STREAK OVARIES)

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MENDELIAN DISORDERS

• THESE ARE MUTATIONS IN SINGLE GENES WITH LARGE EFFECTS

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• INTRODUCTION
• MENDEL'S LAWS
• EXCEPTIONS TO THE LAWS
• TRANSMISSION PATTERNS

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INTRODUCTION

• ALL MENDELIAN DISORDERS ARE A RESULT OF MUTATIONS IN SINGLE GENES THAT HAVE LARGE EFFECTS

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• IT IS ESTIMATED THAT EVERY INDIVIDUAL IS A CARRIER OF FIVE TO EIGHT DELETERIOUS GENES

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INTRODUCTION

• ABOUT 80% TO 85% OF THESE MUTATIONS ARE FAMILIAL

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• THE REMAINDER REPRESENTS NEW MUTATIONS ACQUIRED DE NOVO BY AN AFFECTED INDIVIDUAL

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INTRODUCTION

• MENDELIAN DISORDERS ALSO KNOWN AS SINGLE GENE DISORDERS

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• FOLLOWS THE MENDELIAN PATTERN OF INHERITANCE

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MENDEL’S LAWS

’1^ST LAW’’ LAW OF SEGREGATION

STATES THAT “THE TWO ALLELES FOR A HERITABLE CHARACTER SEGREGATE DURING GAMETE FORMATION AND END UP IN DIFFERENT GAMETES”

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• THEY SEPARATE FROM EACH OTHER

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MENDEL’S LAWS

‘’2^ND LAW’’ LAW OF INDEPENDENT ASSORTMENT

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• ALSO KNOWN AS “LAW OF INHERITANCE“

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STATES THAT “SEPARATE GENES FOR SEPARATE TRAITS ARE PASSED INDEPENDENTLY OF ONE ANOTHER FROM PARENTS TO OFFSPRING”

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MENDEL’S LAWS

• ‘’3^RD LAW’’ LAW OF DOMINANCE

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• STATESTHAT “RECESSIVE ALLELES WILL ALWAYS BE MASKED BY DOMINANT ALLELES”

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• THEREFORE, A CROSS BETWEEN A HOMOZYGOUS DOMINANT AND A HOMOZYGOUS RECESSIVE WILL ALWAYS EXPRESS THE DOMINANT PHENOTYPE

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• WHILE STILL HAVING A HETEROZYGOUS GENOTYPE

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MENDEL’S LAWS

EXCEPTIONS TO MENDEL’S LAW

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• 1. CODOMINANCE

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• 2. HETEROGENEITY

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• 3. LINKED

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TRANSMISSION PATTERNS OF MENDELIAN DISORDERS

• AUTOSOMAL DOMINANT

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• AUTOSOMAL RECESSIVE

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• SEX-LINKED (RECESSIVE), INVOLVING “X” CHROMOSOME

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• NONCLASSIC PATTERNS OF INHERITANCE

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AUTOSOMAL DOMINANT DISORDERS

• AUTOSOMAL DOMINANT DISORDERS ARE MANIFESTED IN THE HETEROZYGOUS STATE

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• ONE PARENT OF AN INDEX CASE IS USUALLY AFFECTED

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• BOTH MALES AND FEMALES ARE AFFECTED

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AUTOSOMAL DOMINANT DISORDERS

• BOTH PARENT CAN TRANSMIT THE CONDITION

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• WHEN AN AFFECTED PERSON MARRIES AN UNAFFECTED ONE

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• EVERY CHILD HAS ONE CHANCE IN TWO OF HAVING THE DISEASE

AUTOSOMAL DOMINANT DISORDERS

• WITH EVERY AUTOSOMAL DOMINANT DISORDER, SOME PROPORTION OF PATIENTS DO NOT HAVE AFFECTED PARENTS

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• SUCH PATIENTS OWE THEIR DISORDER TO NEW MUTATIONS INVOLVING EITHER THE EGG OR THE SPERM FROM WHICH THEY WERE DERIVED

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• THEIR SIBLINGS ARE NEITHER AFFECTED NOR AT INCREASED RISK FOR DISEASE DEVELOPMENT

AUTOSOMAL DOMINANT DISORDERS

• SOME INDIVIDUALS MAY INHERIT THE MUTANT GENE BUT ARE PHENOTYPICALLY NORMAL

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• THIS IS REFERRED TO AS INCOMPLETE PENETRANCE

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• IF A TRAIT IS SEEN IN ALL INDIVIDUALS CARRYING THE MUTANT GENE BUT IS EXPRESSED DIFFERENTLY AMONG INDIVIDUALS

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• THE PHENOMENON IS CALLED VARIABLE EXPRESSIVITY

AUTOSOMAL DOMINANT DISORDERS

• THE MECHANISMS UNDERLYING INCOMPLETE PENETRANCE AND VARIABLE EXPRESSIVITY ARE NOT FULLY UNDERSTOOD

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• MOST LIKELY RESULTS FROM EFFECTS OF OTHER GENES OR ENVIRONMENTAL FACTORS THAT MODIFY THE PHENOTYPIC EXPRESSION OF THE MUTANT ALLELE

AUTOSOMAL DOMINANT DISORDERS

AUTOSOMAL RECESSIVE DISORDERS

• AUTOSOMAL RECESSIVE TRAITS MAKE UP THE LARGEST CATEGORY OF MENDELIAN DISORDERS

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• THEY OCCUR WHEN BOTH ALLELES AT A GIVEN GENE LOCUS ARE MUTATED

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• THE TRAIT DOES NOT USUALLY AFFECT THE PARENTS OF THE AFFECTED INDIVIDUAL, BUT SIBLINGS MAY SHOW THE DISEASE

AUTOSOMAL RECESSIVE DISORDERS

• SIBLINGS HAVE ONE CHANCE IN FOUR OF HAVING THE TRAIT (I.E., THE RECURRENCE RISK IS 25%FOR EACH BIRTH)

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• IF THE MUTANT GENE OCCURS WITH A LOW FREQUENCY IN THE POPULATION

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• THERE IS A STRONG LIKELIHOOD THAT THE AFFECTED INDIVIDUAL (PROBAND) IS THE PRODUCT OF A CONSANGUINEOUS MARRIAGE

AUTOSOMAL RECESSIVECONDITIONS

• THE EXPRESSION OF THE DEFECT TENDS TO BE MORE UNIFORM THAN IN AUTOSOMAL DOMINANT DISORDERS

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• COMPLETE PENETRANCE IS COMMON

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• ONSET IS FREQUENTLY EARLY IN LIFE

AUTOSOMAL RECESSIVE CONDITIONS

• ALTHOUGH NEW MUTATIONS ASSOCIATED WITH RECESSIVE DISORDERS DO OCCUR, THEY ARE RARELY DETECTED CLINICALLY

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• THE INDIVIDUAL WITH A NEW MUTATION IS AN ASYMPTOMATIC HETEROZYGOTE

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• SEVERAL GENERATIONS MAY PASS BEFORE THE DESCENDANTS OF SUCH A PERSON MATE WITH OTHER HETEROZYGOTES AND PRODUCE AFFECTED OFFSPRING

AUTOSOMAL RECESSIVE DISORDERS

• MANY OF THE MUTATED GENES ENCODE ENZYMES

• IN HETEROZYGOTES, EQUAL AMOUNTS OF NORMAL AND DEFECTIVE ENZYME ARE SYNTHESIZED

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• USUALLY THE NATURAL “MARGIN OF SAFETY” ENSURES THAT CELLS WITH HALF THE USUAL COMPLEMENT OF THE ENZYME FUNCTION NORMALLY

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AUTOSOMAL RECESSIVE DISORDERS

• AUTOSOMAL RECESSIVE DISORDERS INCLUDE ALMOST ALL INBORN ERRORS OF METABOLISM

AUTOSOMAL RECESSIVE DISORDERS

X - LINKED RECESSIVE DISORDERS

• MOST SEX-LINKED DISORDERS ARE RECESSIVE

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• GENES LOCATED IN THE “MALE-SPECIFIC REGION OF Y” ARE ALL RELATED TO SPERMATOGENESIS

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• MALES WITH MUTATIONS AFFECTING THE Y-LINKED GENES ARE USUALLY INFERTILE AND HENCE THERE IS NO Y-LINKED INHERITANCE

X – LINKED RECESSIVE DISORDERS

• FEW GENES WITH HOMOLOGUES ON THE X CHROMOSOME HAVE BEEN MAPPED TO THE Y CHROMOSOME

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• BUT ONLY A FEW RARE DISORDERS RESULTING FROM MUTATIONS IN SUCH GENES HAVE BEEN DESCRIBED

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X – LINKED RECESSIVE DISORDERS

• THE Y CHROMOSOME FOR THE MOST PART, IS NOT HOMOLOGOUS TO THE X

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• AND SO MUTANT GENES ON THE X DO NOT HAVE CORRESPONDING ALLELES ON THE Y

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• THUS, THE MALE IS SAID TO BE HEMIZYGOUS FOR X-LINKED MUTANT GENES, SO THESE DISORDERS ARE EXPRESSED IN THE MALE

X – LINKED RECESSIVE DISORDERS

• AN AFFECTED MALE DOES NOT TRANSMIT THE DISORDER TO HIS SONS

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• BUT ALL HIS DAUGHTERS ARE CARRIERS

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• SONS OF HETEROZYGOUS WOMEN HAVE ONE CHANCE IN TWO OF RECEIVING THE MUTANT GENE

X – LINKED RECESSIVE DISORDERS

• THE HETEROZYGOUS FEMALE USUALLY DOES NOT EXPRESS THE FULL PHENOTYPIC CHANGE BECAUSE OF THE PAIRED NORMAL ALLELE

• BECAUSE OF THE RANDOM INACTIVATION OF ONE OF THE X CHROMOSOMES IN THE FEMALE

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• FEMALES HAVE A VARIABLE PROPORTION OF CELLS IN WHICH THE MUTANT X CHROMOSOME IS ACTIVE

X – LINKED RECESSIVE DISORDERS

• THUS, IT IS REMOTELY POSSIBLE FOR THE NORMAL ALLELE TO BE INACTIVATED IN MOST CELLS, PERMITTING FULL EXPRESSION OF HETEROZYGOUS X-LINKED CONDITIONS IN THE FEMALE

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• MUCH MORE COMMONLY THE NORMAL ALLELE IS INACTIVATED IN ONLY SOME OF THE CELLS, AND THUS THE HETEROZYGOUS FEMALE EXPRESSES THE DISORDER PARTIALLY

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X – LINKED RECESSIVE DISORDERS

• DUCHENNE MUSCULAR DYSTROPHY
• HAEMOPHILIA A AND B
• CHRONIC GRANULOMATOUS DISEASE
• GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
• BRUTON'S AGAMMAGLOBULINEMIA

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X – LINKED RECESSIVE DISORDERS

• WISKOTT - ALDRICH SYNDROME
• DIABETES INSIPIDUS
• LESCH - NYHAN SYNDROME
• EHLERS - DANLOS SYNDROME (TYPE 9)
• COLOUR BLINDNESS
• HUNTER SYNDROME

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X – LINKED DOMINANT DISORDERS

• THERE ARE ONLY A FEW X-LINKED DOMINANT CONDITIONS

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• THEY ARE CAUSED BY DOMINANT DISEASE-ASSOCIATED ALLELES ON THE X CHROMOSOME

X – LINKED DOMINANT DISORDERS

• THESE DISORDERS ARE TRANSMITTED BY AN AFFECTED HETEROZYGOUS FEMALE TO HALF HER SONS AND HALF HER DAUGHTERS

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• AFFECTED MALE PARENT TO ALL HIS DAUGHTERS BUT NONE OF HIS SONS, IF THE FEMALE PARENT IS UNAFFECTED

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• VITAMIN D–RESISTANT RICKETS IS AN EXAMPLE OF THIS TYPE OF INHERITANCE

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COMPLEX MULTIGENIC DISORDERS

• COMPLEX MULTIGENETIC DISORDERS OCCUR WHEN 2 OR MORE GENES (POLYMORPHISMS), EACH WITH A MODEST EFFECT AND LOW PENETRANCE ARE CO-INHERITED

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• IT RESULTS FROM THE COLLECTIVE INHERITANCE OF MANY POLYMORPHISMS

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• DIFFERENT POLYMORPHISMS VARY IN SIGNIFICANCE

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COMPLEX MULTIGENIC DISORDERS

• ARE CAUSED BY INTERACTIONS BETWEEN VARIANT FORMS OF GENES AND ENVIRONMENTAL FACTORS

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• A GENE THAT HAS AT LEAST TWO ALLELES, EACH OF WHICH OCCURS AT A FREQUENCY OF AT LEAST 1% IN THE POPULATION IS POLYMORPHIC

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• EACH VARIANT ALLELE IS REFERRED TO AS A POLYMORPHISM

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COMPLEX MULTIGENIC DISORDERS

• ASSIGNING A DISEASE TO THIS MODE OF INHERITANCE MUST BE DONE WITH CAUTION

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• IT DEPENDS ON MANY FACTORS BUT FIRST ON FAMILIAL CLUSTERING AND A RANGE OF LEVELS OF SEVERITY OF A DISEASE IS SUGGESTIVE OF A COMPLEX MULTIGENIC DISORDER

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• EXCLUSION OF MENDELIAN AND CHROMOSOMAL MODES OF TRANSMISSION MUST BE DONE

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SINGLE-GENE DISORDERS WITH�NONCLASSIC INHERITANCE

• TRANSMISSION OF CERTAIN SINGLE-GENE DISORDERS DOES NOT FOLLOW CLASSIC MENDELIAN PRINCIPLES

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• THIS GROUP OF DISORDERS CAN BE CLASSIFIED INTO FOUR CATEGORIES:

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• 1. DISEASES CAUSED BY TRINUCLEOTIDE-REPEAT MUTATIONS

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• 2. DISORDERS CAUSED BY MUTATIONS IN MITOCHONDRIAL GENES

SINGLE-GENE DISORDERS WITH�NONCLASSIC INHERITANCE

• 3. DISORDERS ASSOCIATED WITH GENOMIC IMPRINTING

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• 4. DISORDERS ASSOCIATED WITH GONADAL MOSAICISM

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TRINUCLEOTIDE-REPEAT MUTATIONS�

• EXPANSION OF TRINEUCLOTIDE REPEATS IS AN IMPORTANT GENETIC CAUSE OF HUMAN DISEASES

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• CAUSATIVE MUTATIONS ARE ASSOCIATED WITH THE EXPANSION OF A STRETCH OF TRINUCLEOTIDES THAT USUALLY SHARE THE NUCLEOTIDES G AND C

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• THE EXPANSION OF THE TRINUCLEOTIDE SEQUENCE ABOVE A CERTAIN THRESHOLD IMPAIRS GENE FUNCTION

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TRINUCLEOTIDE-REPEAT MUTATIONS

• EXPANSION DEPENDS STRONGLY ON THE SEX OF THE TRANSMITTING PARENT

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• IN THE FRAGILE X SYNDROME, EXPANSIONS OCCUR DURING OOGENESIS

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• IN HUNTINGTON DISEASE THEY OCCUR DURING SPERMATOGENESIS

TRINUCLEOTIDE-REPEAT MUTATIONS

• THE UNSTABLE TRINUCLEOTIDE REPEATS CAUSE DISEASES BY

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• (1) LOSS OF FUNCTION OF THE AFFECTED GENE, TYPICALLY BY TRANSCRIPTION SILENCING, AS IN FRAGILE X SYNDROME

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• IN SUCH CASES THE REPEATS ARE GENERALLY IN NON-CODING PART OF THE GENE

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TRINUCLEOTIDE-REPEAT MUTATIONS

• (2) A TOXIC GAIN OF FUNCTION BY ALTERATIONS OF PROTEIN STRUCTURE AS IN HUNTINGTON DISEASE AND SPINOCEREBELLAR ATAXIAS

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• IN SUCH CASES THE EXPANSIONS OCCUR IN THE CODING REGIONS OF THE GENES

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TRINUCLEOTIDE-REPEAT MUTATIONS

• (3) A TOXIC GAIN OF FUNCTION MEDIATED BY mRNA AS IS SEEN IN FRAGILE X TREMOR-ATAXIA SYNDROME

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• THE NONCODING PARTS OF THE GENE ARE AFFECTED

TRINUCLEOTIDE-REPEAT MUTATIONS

• FRAGILE X SYNDROME IS THE SECOND MOST COMMON GENETIC CAUSE OF MENTAL RETARDATION AFTER DOWN SYNDROME

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• IT IS CAUSED BY A TRINUCLEOTIDE MUTATION IN THE FAMILIAL MENTAL RETARDATION-1 (FMR1) GENE

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• HAS A FREQUENCY OF 1 IN 1550 FOR AFFECTED MALE AND 1 IN 8000 FOR AFFECTED FEMALES

TRINUCLEOTIDE-REPEAT MUTATIONS

• THE AFFECTED MALES ARE MENTALLY RETARDED, WITH AN IQ IN THE RANGE OF 20 TO 60

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• THEY EXPRESS A CHARACTERISTIC PHYSICAL PHENOTYPE THAT INCLUDES A LONG FACE WITH A LARGE MANDIBLE, LARGE EVERTED EARS, AND LARGE TESTICLES (MACRO-ORCHIDISM)

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• HYPEREXTENSIBLE JOINTS, A HIGH ARCHED PALATE, AND MITRAL VALVE PROLAPSE NOTED IN SOME PATIENTS

TRINUCLEOTIDE-REPEAT MUTATIONS

• THE MOST DISTINCTIVE FEATURE IS MACRO-ORCHIDISM, WHICH IS OBSERVED IN AT LEAST 90% OF AFFECTED POSTPUBERTAL MALES

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• AS WITH ALL X-LINKED DISEASES, FRAGILE X SYNDROME AFFECTS MALES BUT;

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• 20% OF MALES ARE CLINICALLY AND CYTOGENETICALLY

NORMAL (NORMAL TRANSMITTING MALES)

TRINUCLEOTIDE-REPEAT MUTATIONS

• 30% TO 50% OF CARRIER FEMALES ARE AFFECTED (I.E., MENTALLY RETARDED)

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• A NUMBER MUCH HIGHER THAN THAT SEEN IN OTHER X-LINKED RECESSIVE DISORDERS

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• BROTHERS OF TRANSMITTING MALES ARE AT A 9% RISK OF HAVING MENTAL RETARDATION, WHEREAS GRANDSONS OF TRANSMITTING MALES INCUR A 40% RISK (POSITION OF THE INDIVIDUAL IN THE PEDIGREE)

TRINUCLEOTIDE-REPEAT MUTATIONS

• FRAGILE X SYNDROME WORSEN WITH EACH SUCCESSIVE GENERATION

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• THE MUTATION BECOMES INCREASINGLY DELETERIOUS AS IT IS TRANSMITTED FROM A MAN TO HIS GRANDSONS AND GREAT-GRANDSONS (ANTICIPATION)

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• LINKAGE STUDIES LOCALIZED THE MUTATION RESPONSIBLE FOR THIS DISEASE TO XQ27.3, WITHIN THE CYTOGENETICALLY ABNORMAL REGION

TRINUCLEOTIDE-REPEAT MUTATIONS

• WITHIN THIS REGION LIES THE FMR1 GENE, CHARACTERIZED BY MULTIPLE TANDEM REPEATS OF THE NUCLEOTIDE SEQUENCE CGG

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• IN THE NORMAL POPULATION, THE NUMBER OF CGG REPEATS IS SMALL, RANGING FROM 6 TO 55 (AVERAGE, 29)

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TRINUCLEOTIDE-REPEAT MUTATIONS

• NORMAL TRANSMITTING MALES AND CARRIER FEMALES CARRY 55 TO 200 CGG REPEATS.

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• EXPANSIONS OF THIS SIZE ARE CALLED PREMUTATIONS

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• IN CONTRAST, AFFECTED INDIVIDUALS HAVE AN EXTREMELY LARGE EXPANSION OF THE REPEAT REGION (200 TO 4000 REPEATS, FULL MUTATIONS)

TRINUCLEOTIDE-REPEAT MUTATIONS

• DURING THE PROCESS OF OOGENESIS, BUT NOT SPERMATOGENESIS, PREMUTATIONS CAN BE CONVERTED TO MUTATIONS BY TRIPLET-REPEAT AMPLIFICATION

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• THE MOLECULAR BASIS OF MENTAL RETARDATION AND OTHER SOMATIC CHANGES IS RELATED TO A LOSS OF FUNCTION OF THE FAMILIAL MENTAL RETARDATION PROTEIN (FMRP)

MUTATIONS IN MITOCHONDRIAL GENES

• A FEATURE UNIQUE TO mtDNA IS MATERNAL INHERITANCE

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• THIS PECULIARITY EXISTS BECAUSE OVA CONTAIN NUMEROUS MITOCHONDRIA WITHIN THEIR ABUNDANT CYTOPLASM

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• WHEREAS SPERMATOZOA CONTAIN FEW, IF ANY

MUTATIONS IN MITOCHONDRIAL GENES

• mtDNA COMPLEMENT OF THE ZYGOTE IS DERIVED ENTIRELY FROM THE OVUM

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• MOTHERS TRANSMIT mtDNA TO ALL THEIR OFFSPRING, MALE AND FEMALE

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• DAUGHTERS BUT NOT SONS TRANSMIT THE DNA FURTHER TO THEIR PROGENY

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MUTATIONS IN MITOCHONDRIAL GENES

• HUMAN mtDNA CONTAINS 37 GENES

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• 13 GENES ENCODE SUBUNITS OF THE RESPIRATORY CHAIN ENZYMES

• mTDNA ENCODES ENZYMES INVOLVED IN OXIDATIVE PHOSPHORYLATION

MUTATIONS IN MITOCHONDRIAL GENES

• MUTATIONS AFFECTING THESE GENES EXERT THEIR DELETERIOUS EFFECTS PRIMARILY ON THE ORGANS MOST DEPENDENT ON OXIDATIVE PHOSPHORYLATION

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• ORGANS SUCH AS THE CENTRAL NERVOUS SYSTEM, SKELETAL MUSCLE, CARDIAC MUSCLE, LIVER, AND KIDNEYS

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MUTATIONS IN MITOCHONDRIAL GENES

• LEBER HEREDITARY OPTIC NEUROPATHY IS A PROTOTYPE OF THIS TYPE OF DISORDER

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• IT IS A NEURODEGENERATIVE DISEASE THAT MANIFESTS AS A PROGRESSIVE BILATERAL LOSS OF CENTRAL VISION

MUTATIONS IN MITOCHONDRIAL GENES

• VISUAL IMPAIRMENT IS FIRST NOTED BETWEEN AGES 15 AND 35, LEADING EVENTUALLY TO BLINDNESS

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• CARDIAC CONDUCTION DEFECTS AND MINOR NEUROLOGIC MANIFESTATIONS HAVE ALSO BEEN OBSERVED IN SOME FAMILIES

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GENOMIC IMPRINTING

• IMPORTANT FUNCTIONAL DIFFERENCES EXIST BETWEEN THE PATERNAL ALLELE AND THE MATERNAL ALLELE

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• THESE DIFFERENCES RESULT FROM AN EPIGENETIC PROCESS CALLED IMPRINTING

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• IMPRINTING SELECTIVELY INACTIVATES EITHER THE MATERNAL OR PATERNAL ALLELE

GENOMIC IMPRINTING

• IMPRINTING IS TRANSCRIPTIONAL SILENCING OF THE MATERNAL ALLELE OR THE PATERNAL ALLELE

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• IT OCCURS DURING GAMETOGENESIS IN THE OVUM OR THE SPERM

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• IMPRINTING IS ASSOCIATED WITH EPIGENIC DIFFERENTIAL PATTERNS OF DNA METHYLATION AT CG NUCLEOTIDES

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GENOMIC IMPRINTING

• OTHER MECHANISMS INCLUDE HISTONE H4 DEACETYLATION AND METHYLATION

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• GENOMIC IMPRINTING IS BEST ILLUSTRATED BY CONSIDERING PRADER-WILLI AND ANGELMAN SYNDROMES

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• ORIGINALLY BELIEVED TO BE UNRELATED UNTIL THE GENETIC LESIONS RESPONSIBLE FOR THEM WERE MAPPED TO THE SAME LOCATION

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GENOMIC IMPRINTING

PRADER-WILLI SYNDROME

• IS CHARACTERIZED BY MENTAL RETARDATION, SHORT STATURE, HYPOTONIA, PROFOUND HYPERPHAGIA, OBESITY, SMALL HANDS AND FEET, AND HYPOGONADISM

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• 65% TO 70% OF CASES ARE ASSOCIATED WITH AN INTERSTITIAL DELETION OF BAND q12 IN THE LONG ARM OF CHROMOSOME 15, DEL(15)(q11.2q13)

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• IN ALL CASES THE DELETION AFFECTS THE PATERNALLY DERIVED CHROMOSOME 15

GENOMIC IMPRINTING

ANGELMAN SYNDROME

• ARE ALSO MENTALLY RETARDED, BUT IN ADDITION THEY PRESENT WITH ATAXIC GAIT, SEIZURES, AND INAPPROPRIATE LAUGHTER

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• BECAUSE OF THEIR LAUGHTER AND ATAXIA, THEY HAVE BEEN REFERRED TO AS “HAPPY PUPPETS”

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GONADAL MOSAICISM

• IN EVERY AUTOSOMAL DOMINANT DISORDER SOME PATIENTS DO NOT HAVE AFFECTED PARENTS

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• IN SUCH PATIENTS THE DISORDER RESULTS FROM A NEW MUTATION IN THE EGG OR THE SPERM FROM WHICH THEY WERE DERIVED

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• IN SOME AUTOSOMAL DOMINANT DISORDERS PHENOTYPICALLY NORMAL PARENTS HAVE MORE THAN ONE AFFECTED CHILD

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• THIS CLEARLY VIOLATES THE LAWS OF MENDELIAN INHERITANCE

GONADAL MOSAICISM

• GONODAL MOSAICISM RESULTS FROM A MUTATION THAT OCCURS POSTZYGOTICALLY DURING EARLY (EMBRYONIC) DEVELOPMENT

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• IF THE MUTATION AFFECTS ONLY CELLS DESTINED TO FORM THE GONADS, THE GAMETES CARRY THE MUTATION

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• BUT THE SOMATIC CELLS OF THE INDIVIDUAL ARE COMPLETELY NORMAL

GONADAL MOSAICISM

• PHENOTYPICALLY NORMAL PARENT WHO HAS GONADAL MOSAICISM CAN TRANSMIT THE DISEASE-CAUSING MUTATION TO THE OFFSPRING THROUGH THEIR MUTATED GAMETES

• THERE IS A POSSIBILITY THAT MORE THAN ONE CHILD OF SUCH A PARENT WOULD BE AFFECTED, BECAUSE THE PROGENITOR CELLS OF THE GAMETES CARRY THE MUTATION

MOLECULAR DIAGNOSIS OF GENETIC DISEASES

• DISEASE CAUSING GENETIC ANOMALIES RANGE IN SIZE FROM SINGLE BASE SUBSTITUTIONS UP TO GAINS OR LOSSES OF ENTIRE CHROMOSOMES

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• MAY ALSO VARY WIDELY IN FREQUENCY AMONG ETHNIC GROUPS

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• IN CHOOSING THE APPROPRIATE DIAGNOSTIC TECHNIQUE IT IS CRITICAL TO FIRST UNDERSTAND THE SPECTRUM OF GENETIC ANOMALIES THAT ARE RESPONSIBLE FOR THE DISEASES IN THE PATIENT POPULATION UNDER STUDY

MOLECULAR DIAGNOSIS OF GENETIC DISEASES

• TESTING FOR INHERITED ALTERATIONS MAY BE REQUIRED AT ANY AGE, DEPENDING ON CLINICAL PRESENTATION

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• GENERALLY, MOST TESTING IS PERFORMED DURING THE PRENATAL OR POSTNATAL/CHILDHOOD PERIODS

MOLECULAR DIAGNOSIS OF GENETIC DISEASES

• PRENATAL TESTING SHOULD BE OFFERED FOR ALL FETUSES AT RISK FOR A CYTOGENETIC ABNORMALITY

• ADVANCED MATERNAL AGE
• A PARENT KNOWN TO CARRY A BALANCED CHROMOSOMAL REARRANGEMENT
• FETAL ANOMALIES OBSERVED ON ULTRASOUND
• ROUTINE MATERNAL BLOOD SCREENING, INDICATING AN INCREASED RISK OF DOWN SYNDROME OR OTHER TRISOMIES

MOLECULAR DIAGNOSIS OF GENETIC DISEASES

• PARENTS KNOWN TO BE AT RISK FOR HAVING A CHILD WITH A GENETIC DISORDER

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• CAN CHOOSE TO HAVE GENETIC TESTING PERFORMED ON EMBRYOS CREATED IN VITRO PRIOR TO UTERINE IMPLANTATION

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• ELIMINATING THE CHANCE OF GENERATIONAL TRANSMISSION OF A FAMILIAL DISEASE

MOLECULAR DIAGNOSIS OF GENETIC DISEASES

NEWBORNS OR CHILDREN, INDICATIONS MAY BE AS FOLLOWS:

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• MULTIPLE CONGENITAL ANOMALIES

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• SUSPICION OF A METABOLIC SYNDROME

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• UNEXPLAINED MENTAL RETARDATION AND/OR DEVELOPMENTAL DELAY

MOLECULAR DIAGNOSIS OF GENETIC DISEASES

• SUSPECTED ANEUPLOIDY (E.G., FEATURES OF DOWN SYNDROME) OR OTHER SYNDROMIC CHROMOSOMAL ABNORMALITY (E.G., DELETIONS, INVERSIONS)

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• SUSPECTED MONOGENIC DISEASE, WHETHER PREVIOUSLY DESCRIBED OR UNKNOWN

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MOLECULAR DIAGNOSIS OF GENETIC DISEASES

• IN OLDER PATIENTS, TESTING IS FOCUSED TOWARD GENETIC DISEASES THAT MANIFEST AT LATER STAGES OF LIFE

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• INDICATIONS INCLUDE:

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• INHERITED CANCER SYNDROMES (TRIGGERED BY EITHER FAMILY HISTORY OR AN UNUSUAL CANCER PRESENTATION)

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MOLECULAR DIAGNOSIS OF GENETIC DISEASES

• ATYPICALLY MILD MONOGENIC DISEASE (E.G., ATTENUATED CYSTIC FIBROSIS)

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• NEURODEGENERATIVE DISORDERS (E.G., FAMILIAL ALZHEIMER DISEASE, HUNTINGTON DISEASE)

THE END

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THANK YOU