Poulation genetics

Question 1

What is Linkage Analysis?

Answer 1

Linkage analysis is a method for linking heritable traits to their chromosomal location. It relies on the tendency for genes and genetic markers to be inherited together at meiosis because they are located nearby on the same chromosome

Question 2

What types of disorders is Linkage Analysis best suited for?

Answer 2

Linkage analysis is best suited for highly penetrant monogenic disorders with Mendelian inheritance. It is also suitable for single gene defects in families. While historically used mostly for major effect genes, linkage analysis methods can also be applied to complex diseases using model-free or non-parametric approaches.

Question 3

What are the typical requirements for conducting a Linkage Analysis study? A: Linkage analysis typically requires large, multi-generational families

Answer 3

Detailed pedigree information is valuable. Researchers need to identify many families with several affected generations. It also requires collecting families where the phenotype of interest segregates and the scoring of meioses as recombinant or non-recombinant for the locus in question.

Question 4

What is a LOD score and what does it measure in Linkage Analysis

Answer 4

A LOD score (Logarithm of the Odds) is a measure for the likelihood of linkage. It is the logarithm of the ratio of the odds that two loci are linked with a specified recombination frequency (θ) to the odds that they are unlinked. Positive LOD scores favour the presence of linkage; negative scores indicate linkage is less likely. LOD scores can be added across families

Question 5

What are the significance thresholds for LOD scores?

Answer 5

A LOD score higher than 3.0 is generally accepted as evidence for linkage. This corresponds to odds of 1000:1 favouring linkage. A LOD score lower than -2 is accepted as evidence against linkage (exclusion). Values between -2 and +3 are inconclusive

Question 6

: How does recombination affect Linkage Analysis?

Answer 6

Recombination can take place during meiosis, separating a marker and a disease gene. The further apart two loci are, the more likely recombination is. Linkage analysis requires scoring meioses to see if recombination occurred. The recombination fraction (θ) in a pedigree is the frequency with which a crossover occurs between two loci. If θ = 0.5, the loci are not linked. If there are no recombinants (θ=0), the highest LOD score is observed.

Question 7

What are the main types of Linkage Analysis methods?

Answer 7

The main types include Parametric linkage analysis (standard LOD score analysis) and Non-parametric linkage analysis (model-free). Affected Sib Pair (ASP) analysis is a common non-parametric method. Autozygosity mapping is a form of linkage analysis used in consanguineous families.

Question 8

What is the difference between Parametric and Non-parametric Linkage Analysis?

Answer 8

Parametric linkage analysis requires specifying parameters like the mode of inheritance, gene frequencies, and penetrance. It is used for simple Mendelian disorders but is prone to errors and problems with locus heterogeneity and specifying the genetic model. Non-parametric linkage analysis does not require an inheritance model and makes no assumptions about other genes involved in disease risk. Its principle is that affected family members will co-inherit the disease region from a common ancestor more often than by chance. Non-parametric methods are generally considered more robust

Question 9

What are the advantages of Linkage Analysis?

Answer 9

Linkage studies are good for localising areas of disease risk across the genome. They can be used to study multiple genetic markers simultaneously. They are suitable for single gene defects in families. They can help determine if a phenotype is caused by a single gene or mutations in other genes. Linkage analysis can also be useful in diagnosis using flanking markers. Linkage is not affected by population structur

Question 10

What are the disadvantages of Linkage Analysis?

Answer 10

Disadvantages include the need to identify many families with several affected generations, which is difficult for late-onset diseases. Linkage studies are less helpful for complex traits (using parametric methods). LOD score analysis requires precise genetic models and is vulnerable to errors like misdiagnosis, reduced penetrance, switched samples, and non-paternity. They have limits of resolution dependent on the number of meioses. Detecting loci with modest effects requires large numbers of ASPs

Question 11

What are some applications of Linkage Analysis in diagnostic laboratories?

Answer 11

Linkage analysis can be applied in diagnostic labs when the causative pathogenic variant hasn’t been identified or quantitative deletion analysis isn’t feasible. It requires the locus to be known and the clinical diagnosis clearly defined. It uses flanking markers to identify the high-risk haplotype. Examples include identifying high-risk haplotypes in DMD where the mutation isn’t found, clarifying SMA carrier risk when a parent has two SMN1 copies on one allele, and Huntington’s disease (HD) using the linkage exclusion method for prenatal testing

Question 12

How is Next-Generation Sequencing (NGS) impacting Linkage Analysis?

Answer 12

Whole exome (WES) and whole genome sequencing (WGS) are powerful tools to identify candidate disease variants. Combining WES/WGS with linkage analysis provides statistical support for identified variants being associated with the disease

Question 13

What is Linkage Disequilibrium (LD)?

Answer 13

Linkage disequilibrium (LD) is the non-random association of alleles at two or more loci with a frequency greater than expected by chance. It means that combinations of alleles or genetic markers occur in a population more often or less often than expected from random formation based on allele frequencies. If loci are in linkage equilibrium, their genotypes appear independently

Question 14

What are the main causes of Linkage Disequilibrium?

Answer 14

LD can be due to natural selection or chance. It can also result from a new mutation arising on a founder chromosome, population structure (like subdivision, inbreeding, non-random mating), genetic drift, gene flow between populations with different allele frequencies, and population history (older populations tend to have shorter segments of LD

Question 15

How does recombination affect Linkage Disequilibrium over time

Answer 15

Over time, recombination between loci gradually reduces LD as alleles that were shared on an ancestral chromosome are separated. It can be harder to find LD in older populations. Areas of the genome with a lower recombination rate can maintain LD for longer

Question 16

What is an Association Study?

Answer 16

Association studies compare cases (people with a genetic trait/disease) to controls (people without) to identify a statistical relationship (association) between a particular allele, genotype, haplotype, or polymorphism(s) and the trait. The aim is to identify disease susceptibility gene variants

Question 17

What types of diseases are Association Studies suitable for?

Answer 17

Association studies can identify association in complex diseases like diabetes and hypertension. They can also be used for studying rare diseases and are particularly powerful for detecting genes associated with multifactorial disease like polygenic disorders at a population level

Question 18

What is GWAS and how does it work?

Answer 18

GWAS (Genome-Wide Association Study) is an approach that rapidly scans genetic markers (typically SNPs) across the genomes of many people to find variations associated with a trait or disease. It is generally based on a case-control design, comparing genetic variants in people with the disease (cases) to similar people without (controls). It is a ‘hypothesis free’ approach that investigates the entire genome. GWAS usually uses SNP arrays to read millions of genetic variants. If a variant is more frequent in cases, it’s associated with the disease. Associated SNPs mark a region influencing risk

Question 19

What are the potential causes for finding a positive association in an Association Study?

Answer 19

There are four main causes for a positive association: 1. Chance. 2. False association due to Linkage Disequilibrium between the studied marker and the true disease-causing variant. 3. Bias resulting from population stratification. 4. True association, where the genetic variant is important in disease causation.

Question 20

What are the advantages of Association Studies?

Answer 20

Association studies can be used for studying rare diseases, testing specific markers, and investigating gene-gene or gene-environment interactions. GWAS is likely always a more powerful method for detecting genes associated with multifactorial disease compared to linkage analysis in human populations. They have fine genetic resolution

Question 21

What are the disadvantages of Association Studies (including GWAS)?

Answer 21

Association studies cannot test causality; they only measure statistical associations. They are prone to confounding variables, particularly population stratification. They can be expensive. GWAS requires necessity for multiple testing correction, making the statistical threshold for significance very low and hard to reach. They need large studies to have sufficient power. Most GWAS identify SNPs conferring only small effects, contributing to missing heritability. GWAS limitations include potential for false positives, lack of information on gene function, insensitivity to rare variants, need for large sample sizes, and potential biases from selection/genotyping error

Question 22

What is the primary difference between Linkage Analysis and Association Analysis?

Answer 22

The primary difference is that linkage analysis looks at the relation between the transmission of a locus and the disease/trait within families, whereas association analysis focuses on the relation between a specific allele/variant and the disease/trait within a populatio

Question 23

What are some benefits to human health from GWAS discoveries?

Answer 23

GWAS are contributing to personalized medicine. They have identified genetic variations contributing to risk for conditions like type 2 diabetes, Parkinson’s disease, heart disorders, obesity, Crohn’s disease, and prostate cancer. They have also identified variants influencing response to anti-depressant medications.

Question 24

How does genetic screening differ from genetic testing?

Answer 24

Genetic screening targets populations/sub-populations rather than at-risk individuals to detect future disease risks in individuals/progeny for which established preventive interventions exist

Question 25

According to the World Health Organisation (WHO), what is the definition of "Screening"

Answer 25

Screening refers to the use of simple tests across an apparently healthy population in order to identify individuals who have risk factors or early stages of disease, but do not yet have symptoms

Question 26

What are some examples of conditions for which genetic screening targets populations/sub-populations?

Answer 26

Examples include newborn screening for phenylketonuria (PKU) and cystic fibrosis (CF), and carrier screening for sickle cell disease

Question 27

What is the Newborn Blood Spot (NBS) screening programme?

Answer 27

Involves a series of biochemical/genetic tests carried out on blood spots taken from 5 day old babies to indicate whether the infant is affected with a serious medical disorder

Question 28

What is the Fetal Anomaly Screening Programme (FASP)

Answer 28

A detailed ultrasound scan during pregnancy, looking in detail at fetal anatomy; Fetal abnormalities are associated with chromosomal abnormalities and invasive Cytogenetic testing is offered

Question 29

When does the Royal College of Pathologists guidance recommend prenatal microarray testing?

Answer 29

If one or more structural abnormalities are identified by ultrasound or if an isolated nuchal translucency is greater than or equal to 3.5mm within a specific gestational age range

Question 30

What does the Down Syndrome Screening Programme involve?

Answer 30

Maternal blood test during pregnancy for biochemical markers associated with increased risk of chromosomal abnormality; invasive Cytogenetics testing is offered if the serum risk is greater than 1:150

Question 31

What is a key ethical issue around preconception screening/prenatal testing related to individual choice? A

Answer 31

Reproductive autonomy - individuals have a right to make informed choices, supported by non-directive counselling

Question 32

What is a potential benefit of screening programmes?

Answer 32

Improved prognosis

Question 33

What is a potential disadvantage of genetic screening programmes specifically?

Answer 33

Anxiety and morbidity for false positive result

Question 34

According to ESHG recommendations (2003), what is an advantage of genetic screening programmes related to pre-symptomatic detection?

Answer 34

Can allow pre-symptomatic detection of disease or susceptibility where options for prevention, early diagnosis, care, and treatment exist

Question 35

How can detection of carrier status be beneficial?

Answer 35

Can enable individuals to make informed reproductive or lifestyle decisions

Question 36

Why is full gene sequencing not recommended by ACMG in screening

Answer 36

VOUS introduction

Question 37

What are the issues with using WGS/WES as population screening currently?

Answer 37

While potentially cost-effective, it lacks equity of access

Question 38

What are the two main groups of inherited cardiac conditions?

Answer 38

The two main groups are Cardiomyopathies and Inherited cardiac arrhythmias

Question 39

What are Cardiomyopathies?

Answer 39

Cardiomyopathies are disorders of cardiac muscle not caused by coronary artery disease, increased blood pressure, or problems with the heart’s valves. They involve cardiac muscle disease and/or measurable deterioration of cardiac muscle function

Question 40

How are Cardiomyopathies classified according to WHO guidelines?

Answer 40

*Dilated Cardiomyopathy (DCM) *Hypertrophic Cardiomyopathy (HCM) *Restricted cardiomyopathy (RCM) *Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) *Left Ventricular Non-Compaction (LVNC)

Question 41

What are some non-genetic causes of conditions that can resemble cardiomyopathies?

Answer 41

Non-genetic causes can include hypertension, ischemia, inflammation, and exposure to certain therapies or drug abuse

Question 42

What are some potential symptoms of cardiomyopathies?

Answer 42

Symptoms may include palpitations, shortness of breath, chest pain, and blackouts. They can also lead to sudden cardiac death (SCD). Some individuals may be asymptomatic or subclinical.

Question 43

What types of genes are usually involved in the genetic causes of cardiomyopathies?

Answer 43

usually involve genes encoding muscle proteins, such as actin, myosin, and titin

Question 44

What are some common paediatric cardiomyopathy disorders?

Answer 44

Common paediatric disorders include Noonan syndrome, Danon disease, cardiac glycogenesis, and Barth syndrome

Question 45

hat is the physiological change seen in Dilated Cardiomyopathy (DCM)?

Answer 45

DCM involves an increase in myocardial mass, a reduction in ventricular (usually left) wall thickness, a globular shape to the heart, diffuse endocardial thickening, and decreased force of contraction

Question 46

What is the most prevalent cardiomyopathy and a common reason for cardiac transplantation?

Answer 46

Dilated Cardiomyopathy (DCM) is the most prevalent cardiomyopathy and a reason for cardiac transplantation in adults and children

Question 47

What is Familial DCM defined as?

Answer 47

Familial DCM is diagnosed if ≥2 relatives have Idiopathic DCM or SCD occurs at a young age within the family

Question 48

What are some triggers that can unmask familial DCM?

Answer 48

Triggers may include alcohol, infection, medication, and pregnancy

Question 49

What are the inheritance patterns for DCM?

Answer 49

Inheritance for DCM is variable, including autosomal dominant (AD), autosomal recessive (AR), X-linked, and mitochondrial.

Question 50

What is the most common genetic cause of inherited DCM

Answer 50

Titin (TTN) accounts for approximately 1/3 of inherited cases, primarily due to truncating variants in the A-band

Question 51

Name some other genes frequently associated with DCM.

Answer 51

Pathogenic variants in genes such as LMNA (6%), MYH7 (4%), and FLNC (2-4%) account for a significant proportion of DCM cases

Question 52

What physiological change is typical in Hypertrophic Cardiomyopathy (HCM)

Answer 52

HCM is typically characterised by asymmetric thickening of the cardiac muscle, most often involving the inter-ventricular septum (in 2/3 of cases)

Question 53

What is dynamic outflow obstruction in HCM?

Answer 53

Obstruction to the outflow of blood from the left ventricle can occur. It is present at rest in 25% of individuals with HCM and can be provoked under certain conditions in 70% of patients

Question 54

What are some presentations of HCM?

Answer 54

Presentations include angina, palpitations, jerky pulse, presyncope, and syncope. It can range from asymptomatic to progressive heart failure or SCD

Question 55

What is a key diagnostic criterion for HCM

Answer 55

Unexplained hypertrophy of the left ventricle (or occasionally the right), typically >15mm in adults, is a key criterion

Question 56

What is the typical inheritance pattern and involved genes in HCM?

Answer 56

HCM is typically inherited in an autosomal dominant (AD) manner with variable penetrance. Most variants are in genes coding for sarcomeric proteins involved in contraction.

Question 57

What are the two most common genes associated with HCM?

Answer 57

The most common genes are MYBPC3 (myosin binding protein C) and MHY7 (β-cardiac myosin heavy chain gene)

Question 58

What physiological change occurs in Restrictive Cardiomyopathy (RCM)?

Answer 58

In RCM, the ventricles become stiff (without necessarily thickening), resisting normal filling with blood

Question 59

What are common symptoms of RCM

Answer 59

Symptoms include fatigue, shortness of breath, oedema and abdominal enlargement, blood clots, arrhythmia, and palpitations

Question 60

How is RCM diagnosed?

Answer 60

Diagnosis involves assessing diastolic dysfunction and eventually heart failure. CMR and echo are used. The rhythmicity and contractility of the heart may be normal

Question 61

Are the genes involved in RCM unique?

Answer 61

Genes involved in HCM are also involved in some cases of RCM, and families with HCM can have individuals with RCM

Question 62

What is the physiological hallmark of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)?

Answer 62

ARVC involves the progressive loss of cardiomyocytes (mainly in the right ventricle) and their replacement with fatty/fibro-fatty tissue, which predisposes to electrical instability.

Question 63

What are the typical presentations of ARVC?

Answer 63

Presentations include ventricular arrhythmias, heart palpitations, syncope, and SCD. These are more common in adolescents and young adults and may be precipitated by exertion

Question 64

What is a common genetic cause of ARVC?

Answer 64

PKP2 is the most common genetic cause of ARVC

Question 65

What are Inherited cardiac arrhythmias?

Answer 65

Inherited arrhythmia syndromes result from disorders in the heart's electrical system

Question 66

What are some inherited cardiac arrhythmia syndromes mentioned?

Answer 66

Examples include Long QT Syndrome (LQT) and Brugada Syndrome (BS)

Question 67

What is the physiological characteristic of Long QT Syndrome (LQT)?

Answer 67

LQT involves a delay at the end of each heartbeat; the heart takes longer than normal to repolarise, which is visible as a delay on the “Q-T” wave of an ECG.

Question 68

What events often trigger symptoms in LQT?

Answer 68

Arrhythmogenic syncope, ventricular tachycardia, cardiac arrest, and SCD typically occur during conditions of either physical or emotional stress.

Question 69

: What genes are typically affected in the most common types (1-3) of LQT?

Answer 69

Types 1 and 2 involve variants in K+ channels (KCNQ1 and KCNH2), while Type 3 involves variants in the Na+ channel (SCN5A). These account for about 75% of cases

Question 70

Types 1 and 2 involve variants in K+ channels (KCNQ1 and KCNH2), while Type 3 involves variants in the Na+ channel (SCN5A). These account for about 75% of cases

Answer 70

BS is characterised by cardiac conduction abnormalities due to ST segment abnormalities on ECG, leading to ventricular fibrillation.

Question 71

What is the main gene associated with Brugada Syndrome?

Answer 71

The SCN5A gene, which encodes the α subunit of the cardiac sodium channel, is the primary gene included on NHS testing panels

Question 72

What type of SCN5A mutations generally cause Brugada syndrome compared to LQT?

Answer 72

SCN5A Loss-of-Function (LOF) mutations generally cause Brugada syndrome. Missense gain-of-function mutations generally cause Long QT syndrome

Question 73

Does genetic testing usually change the clinical diagnosis in the affected individual (proband)?

Answer 73

enetic testing does not usually change the clinical diagnosis in the proband, but knowing the specific gene or variant may predict prognosis or severity.

Question 74

What types of management are used for ICCs?

Answer 74

Management is varied and can include drug treatments, risk management (like avoiding competitive sports), corrective cardiac surgery/procedures, and the use of devices like pacemakers or internal defibrillators

Question 75

What is a significant challenge in cardiac genetic testing related to variant interpretation?

Answer 75

challenges include incomplete penetrance, age-dependent penetrance, "missing heritability," and the difficulty in classifying variants of uncertain significance (VUS) or rare variants specific to a family

Question 76

genetic testing always equally informative across all populations?

Answer 76

Genetic testing is more informative in individuals from European-ancestry populations due to more extensive study, indicating an inequality.

Question 77

What are some non-genetic causes of infertility mentioned in the source?

Answer 77

Non-genetic causes include side effects of medication (e.g. chemotherapy), lifestyle factors (e.g. smoking, alcohol, obesity, stress), maternal age, infections (e.g. mumps), ovulation disorders (e.g. PCOS, thyroid problems, premature ovarian failure), endometriosis, anatomical factors (e.g. uterine abnormalities), injury (e.g. to testicles), and low sperm count and/or mobility

Question 78

How is recurrent miscarriage defined, and what percentage of couples does it affect?

Answer 78

Recurrent miscarriage is defined as the loss of three or more consecutive pregnancies and affects 1% of couples trying to conceive

Question 79

What is Azoospermia?

Answer 79

Azoospermia is defined as the absent sperm in ejaculate

Question 80

What is Oligozoospermia?

Answer 80

Oligozoospermia is defined as a reduced sperm count < 15x10^6/ml.

Question 81

What is the most frequent genetic cause of male infertility?

Answer 81

47,XXY Klinefelter syndrome (KS) is the most frequent genetic cause of male infertility, occurring in 4-6% of cases

Question 82

How is Klinefelter syndrome characterised clinically?

Answer 82

KS is characterised by hypogonadism, gynecomastia (with increased risk of breast cancer), azoospermia or oligospermia, increased levels of gonadotropins and low testosterone levels. It often presents in phenotypically normal men with infertility or low sperm counts

Question 83

How do individuals with 45,X/46,XY mosaicism typically present phenotypically?

Answer 83

90% of patients have normal male external genitalia, while 10% show abnormal genitalia, ambiguous genitalia, or female genitalia.

Question 84

What causes infertility in some cases of 45,X/46,XY mosaicism?

Answer 84

Abnormal gonadal development can result in azoospermia and low testosterone levels. This can sometimes be due to a structurally abnormal Y chromosome (e.g. i(Yp)) that may be lost upon cell division

Question 85

How rare is 46,XX male Disorder of Sex Development (DSD), and how does it usually arise?

Answer 85

46,XX male DSD is rare (1:20,000-25,000 males) and usually arises from the presence of Yp material (often not visible cytogenetically) on an X chromosome, occult XX/XXY mosaicism, inappropriate activity of a gene normally Y-dependent, or stochastic/genetic predisposition.

Question 86

How do SRY-positive (SRY+) 46,XX males typically present after puberty?

Answer 86

Approximately 90% of SRY+ XX testicular DSD males present after puberty with normal pubic hair and penile size but small testes, gynecomastia, and infertility resulting from azoospermia

Question 87

How do SRY-negative (SRY-) 46,XX males typically present?

Answer 87

SRY- XX males tend to present with ambiguous genitalia at birth, such as penoscrotal hypospadias and cryptorchidism. If untreated, they almost always develop gynecomastia around puberty, and are infertile

Question 88

What are Y isochromosomes and how can they affect individuals?

Answer 88

Y isochromosomes are structural abnormalities of the Y chromosome. They are seen in non-mosaic and mosaic forms with a 45,X cell line. The phenotype is variable depending on the 45,X cell line presence/extent, ranging from males with infertility to females with Turner Syndrome features and ambiguous genitalia. They are associated with male infertility due to loss of Azoospermia Factor (AZF) loci

Question 89

What is the consequence of X;autosome translocations for male fertility?

Answer 89

X;autosome translocations almost always lead to spermatogenic arrest due to disruption of the sex vesicle, resulting in azoospermia/infertility.

Question 90

how do structural chromosome rearrangements lead to infertility, particularly in males?

Answer 90

Structural chromosome rearrangements cause the failure to complete synapsis during meiosis, activating the meiotic pachytene checkpoint, which leads to cell death. Spermatogenic cells are more vulnerable, making male carriers more susceptible to infertility

Question 91

Are all males with balanced autosomal rearrangements infertile?

Answer 91

No, whilst balanced structural rearrangements are seen in a higher proportion in infertile males, the majority of males with balanced autosomal rearrangements do not have infertility as a significant number of sperm cells can avoid arrest and complete meiosis

Question 92

What Y chromosome regions are associated with spermatogenic failure due to microdeletions?

Answer 92

Azoospermia Factor (AZF) regions: AZFa, AZFb, and AZFc on the long arm of the Y chromosome

Question 93

Which AZF deletion is considered the most severe, resulting in Sertoli cell-only syndrome (SCOS) and making sperm retrieval not possible?

Answer 93

Complete deletions of AZFa are the most severe (0.5-4% of deletions), resulting in SCOS, bilaterally small testes, and azoospermia.

Question 94

Which is the most frequent Y chromosome microdeletion type? A

Answer 94

AZFc (b2/b4) deletion is the most frequent deletion type, accounting for approximately 80% of deletions

Question 95

What is the clinical phenotype associated with AZFc deletions?

Answer 95

AZFc deletions have a variable clinical phenotype, generally compatible with residual spermatogenesis. Phenotypes range from azoospermia (less severe than AZFa/b) and SCOS to severe/mild oligozoospermia

Question 96

What is Premature ovarian failure (POF) or primary ovarian insufficiency (POI)?

Answer 96

POF/POI is when the ovaries stop functioning normally before the age of 40 years

Question 97

What causes Turner Syndrome?

Answer 97

Turner Syndrome is caused by a completely or partially missing X chromosom

Question 98

hat are some key characteristics of Turner Syndrome?

Answer 98

Characteristics include short stature, delayed puberty, ovarian dysgenesis, hypergonadotropic hypogonadism, infertility, congenital heart defects, and endocrine disorders. Prenatally, it can be associated with cystic hygroma or nuchal thickening

Question 99

How does skewed X-inactivation in X;autosome translocation carriers affect fertility and potentially cause disease?

Answer 99

Balanced female heterozygotes preferentially silence the normal X chromosome. If the breakpoint disrupts a critical region (CR1 or CR2), this can lead to POF. If the breakpoint is within or near a gene on the active derivative chromosome, it can lead to the female being affected by X-linked recessive conditions (e.g. DMD)

Question 100

What is the main genetic cause of Fragile X-associated primary ovarian insufficiency (FXPOI)?

Answer 100

FXPOI is associated with premutation (PM) alleles (59-200 CGG repeats) in the first untranslated exon of the FMR1 gene

Question 101

hat is a counselling consideration for females who are carriers of an FMR1 premutation?

Answer 101

Counselling is required because the premutation can expand into a full mutation size in one generation, carrying a risk of Fragile X syndrome in offspring

Question 102

What is Congenital hypogonadotropic hypogonadism (CHH)?

Answer 102

CHH is caused by gonadotropic releasing hormone deficiency, resulting in central hypothalamic hypogonadism, which leads to incomplete or absent puberty and infertility

Question 103

What are the clinical forms of CHH? A

Answer 103

The three clinical forms are Kallmann syndrome, normosmic CHH, and CHH as part of a complex genetic syndrome (e.g. Bardet-Biedl syndrome, CHARGE syndrome, Prader-Willi syndrome, Waardenburg syndrome)

Question 104

How does Myotonic dystrophy type 1 (DM1) affect fertility in males and females?

Answer 104

In males, 80% have progressive testicular atrophy, with oligoospermia and azoospermia reported in approximately 75%. In females, there is little evidence of gonadal dysfunction, but there is an increase in maternal complications during pregnancy and labour related to uterine dysfunction.

Question 105

What is the initial genetic testing strategy often employed for less specific infertility phenotypes?

Answer 105

Less specific phenotypes are often initially investigated by karyotyping and appropriate molecular testing (e.g. Y chromosome microdeletions in azoospermic males or FMR1 triplet repeat sizing in females with POF)

Question 106

What genetic testing is recommended for products of conception after recurrent miscarriage?

Answer 106

CR and/or chromosomal microarray for products of conception after the 3rd and subsequent consecutive miscarriage. Karyotype of parents is advised if the products show an unbalanced structural rearrangement

Question 107

What is Klinefelter Syndrome?

Answer 107

Klinefelter Syndrome is a sex chromosome aneuploidy characterised by the presence of an extra genetic material in the form of an additional X chromosome. The typical karyotype is 47,XXY.

Question 108

What are the typical effects of the extra X chromosome in Klinefelter Syndrome?

Answer 108

The extra X chromosome typically affects physical, neurodevelopmental, behavioural, and neurocognitive functioning. The severity of these effects is often variable

Question 109

What are some of the most common clinical features of Klinefelter Syndrome?

Answer 109

Common features include hypogonadism and reduced fertility/infertility, decreased testosterone/endocrine function, small testes, gynecomastia, long legs/arms, and tall stature. Many individuals show few detectable symptoms.

Question 110

hat is the most common cause of hypogonadism in males, according to the source?

Answer 110

Klinefelter syndrome

Question 111

What are the reported risk factors for Klinefelter Syndrome?

Answer 111

Maternal (and possibly paternal) age is a risk factor, with a 4-fold increase in prevalence in mothers >40 years

Question 112

What is the mechanism that causes Klinefelter Syndrome?

Answer 112

mechanism is nondisjunction of one X chromosome during meiosis I in the male or meiosis II in the female. There is no parent of origin effect reported.

Question 113

What is Mosaic Klinefelter Syndrome?

Answer 113

Mosaicism in Klinefelter Syndrome can involve different cell lines, such as 47,XXY/46,XY with varying degrees of spermatogenic failure. Cases with 47,XXY/46,XX and clinical features suggesting Klinefelter syndrome are very rare

Question 114

What treatments can be offered for Klinefelter Syndrome?

Answer 114

HRT (Hormone Replacement Therapy) can be offered to those presenting with hypergonadotrophic hypogonadism. ART can be offered for fertility

Question 115

What developmental and behavioural characteristics are associated with XYY Syndrome?

Answer 115

Associated characteristics include speech delay, attention deficit hyperactive disorder, and autistic spectrum disorder. Half of boys may have learning disabilities, delayed speech and language skills, delayed motor skills, and hypotonia

Question 116

What genetic mechanism might contribute to the tall stature in XYY Syndrome?

Answer 116

It is postulated that the increased gene dosage of three SHOX genes (located in the pseudoautosomal region PAR1) leads to tall stature in sex chromosome trisomies like 47,XYY, similar to 47,XXX and 47,XXY. Haplo-insufficiency of the SHOX gene leads to short stature in Turner Syndrome (45,X)

Question 117

What is Turner Syndrome?

Answer 117

Turner syndrome is a common chromosomal abnormality caused by partial or complete X chromosome monosomy. The typical karyotype is 45,X

Question 118

What are some other X chromosome anomalies found in patients with Turner Syndrome besides 45,X

Answer 118

ther anomalies include 46,X,del(Xp), 46,X,i(X)(q10), 46,X,r(X) or other X chromosome structural abnormalities. Approximately 55% of patients have a 45,X karyotype, while the remaining display these other anomalies or mosaicism

Question 119

What is the genetic origin of the X chromosome in most 45,X cases of Turner Syndrome?

Answer 119

In most cases with 45,X, the X chromosome comes from the mother. This may be due to nondisjunction in the father, which is also associated with advanced paternal age

Question 120

Is Turner Syndrome typically inherited?

Answer 120

In most cases, Turner Syndrome is sporadic, and the risk of recurrence is not increased for subsequent pregnancies. Rare exceptions may include the presence of a balanced translocation of the X chromosome in a parent or X mosaicism restricted to the mother's germ cells

Question 121

What are some characteristic physical features of individuals with Turner Syndrome?

Answer 121

Individuals are phenotypically female and typically have short stature, high palate, short and webbed neck, low hairline at the back of the neck, puffiness or swelling of the hands and feet (lymphedema), and hypoplastic widely spaced nipples. Skeletal abnormalities and kidney problems are also mentioned

Question 122

How does Turner Syndrome affect ovarian function?

Answer 122

Turner Syndrome is a cause of gonadal dysfunction, primary amenorrhea, and premature ovarian failure (hypergonadotropic hypogonadism). Individuals typically have streak gonads and infertility. Oocytes undergo apoptosis and disappear at an accelerated rate, often gone by age 2. Failure to develop secondary sex characteristics is typica

Question 123

What are some important medical complications associated with Turner Syndrome?

Answer 123

There can be significant medical problems, particularly cardiovascular malformations. These include a narrowing of the large artery leaving the heart (coarctation of the aorta) or abnormalities of the aortic valve. Complications associated with heart defects can be life-threatening. Hypothyroidism is also mentioned as an associated finding.

Question 124

What is the typical cognitive profile of individuals with Turner Syndrome?

Answer 124

Most girls and women with Turner Syndrome have normal intelligence. However, developmental delays, nonverbal learning disabilities, and behavioural problems are possible and vary among affected individuals

Question 125

What is the medical importance of finding Y-chromosome material in individuals with Turner Syndrome mosaicism?

Answer 125

The presence of Y-chromosome material has a 10% to 30% risk of developing gonadoblastoma. This results in malignancy of streak ovary and an increased risk of developing gonadal tumours and virilisation. Gonadectomy is recommended in mosaics where the presence of the Y chromosome is confirmed, and mosaic cases need assessment for the presence of SRY

Question 126

How might a 45,X/46,XX mosaic karyotype affect the phenotype in Turner Syndrome?

Answer 126

Individuals with Mosaic 45,X/46,XX may have a “milder” phenotype, may be taller, may enter puberty spontaneously, are likely to have secondary amenorrhea/premature menopause, and may be fertile

Question 127

What is the role of the SHOX gene in Turner Syndrome?

Answer 127

he SHOX gene (located in the pseudoautosomal region) is important for bone development and growth. The loss of one copy of this gene likely causes short stature and skeletal abnormalities in women with Turner Syndrome

Question 128

What treatments are available for individuals with Turner Syndrome?

Answer 128

Growth hormone may help a child grow taller. Estrogen replacement therapy is often started around age 12 or 13 to help trigger the development of secondary sexual characteristics. Women who wish to become pregnant may consider using a donor egg. Gonadectomy is recommended in mosaics where the presence of a Y chromosome is confirmed

Question 129

What is the typical phenotype in Triple X Syndrome?

Answer 129

he phenotype is essentially normal. The most common physical features can include tall stature, epicanthal folds, hypotonia, and clinodactyly

Question 130

What causes Triple X Syndrome?

Answer 130

risomy X most commonly occurs as a result of nondisjunction during meiosis. Postzygotic nondisjunction occurs in approximately 20% of cases.

Question 131

How are sex chromosome aneuploidies typically detected prenatally?

Answer 131

In the prenatal setting, they are typically picked up by QF-PCR and confirmed by a follow-up karyotype

Question 132

What was a primary goal of the 100,000 Genomes Project?

Answer 132

To create a new genomic medicine service for the NHS, offering a diagnosis where there wasn't one before and potentially develop new and more effective treatments. It also aimed to enable new medical research by combining genomic sequence data with medical records, and to enable new scientific discovery and medical insights

Question 133

How many genomes were targeted for sequencing in the 100,000 Genomes Project, and from whom?

Answer 133

Roughly 100,000 genomes. This included approximately 25,000 cancer patients (contributing their own and their tumour's genome), about 17,000 people with rare diseases plus two blood relatives of each patient (adding another 50,000 genomes), and a smaller number of patients with severe infections

Question 134

: What kind of findings were communicated back to clinicians and patients in the 100,000 Genomes Project

Answer 134

Relevant findings concerning the participant's main condition were sent back to their doctors. Participants could also opt for feedback on high probability pathogenic findings, and information about 12 'serious and actionable' conditions (e.g., cancer predispositions like FAP, BRCA1/2). Carrier status for non-affected parents of children with rare diseases could also be reported if opted for

Question 135

What is the Genomics England Clinical Interpretation Partnership (GeCIP) and what was its purpose?

Answer 135

The GeCIP was a model allowing funders, researchers, NHS clinicians, and scientists to collaborate. It included over 2250 researchers and was organised into disease-specific and function-specific domains. Its purpose was to drive data analysis, clinical interpretation, and ultimately drive up the fidelity of clinical interpretation

Question 136

What is the aim of the NHS Genomic Medicine Service using WGS?

Answer 136

To support diagnosis, inform and improve treatment pathways, and ultimately improve outcomes for NHS patients in England with known rare diseases and cancer types

Question 137

How are rare disease and cancer cases typically handled in terms of sample sequencing in the NHS GMS WGS service?

Answer 137

For Rare Disorders, Trio analysis (patient and parents) of germline DNA is usually performed. For Cancer, tumour and germline DNA samples are sequenced simultaneously

Question 138

What software is used for analysis in the NHS GMS WGS service?

Answer 138

Congenica is used as analysis software for Rare Disorders. BSVI is used for Cancer Cases, though some labs have their own software. The programme Exomiser is also used for rare disease panels to help identify potential causative variants based on the patient's phenotype

Question 139

How does the NHS GMS pipeline identify potentially disease-causing variants?

Answer 139

The pipeline applies a variant tiering system to identify variants likely to be disease-causing. Tiering primarily includes variants within protein-coding genes and near exon boundaries. It also detects CNVs ≥2 kb and Short Tandem Repeat (STR) expansions at selected loc

Question 140

Why is trio analysis (patient and parents) preferred for rare disease testing in the NHS GMS?

Answer 140

To make variant interpretation more straightforward and to reduce the number of amended reports and delays caused by waiting for parental samples

Question 141

Why is the patient consent process particularly important for WGS in the NHS GMS?

Answer 141

Because incidental findings can occasionally occur, and families need to be aware that this is a possibility

Question 142

What are the target turnaround times (TAT) for results in the NHS GMS WGS service?

Answer 142

For Cancer and Urgent Rare Disease cases, the target is 21 calendar days. For Routine Rare Disease cases, the target is 42 calendar days. (Note: Sources indicate GLHs currently struggle to meet these times).

Question 143

What was the Deciphering Developmental Delay (DDD) study?

Answer 143

A study of nearly 14,000 families with severe, undiagnosed developmental disorders using exome sequencing and array detection. It was pioneering for combining discovery and diagnosis on the same data

Question 144

What were some key findings from the DDD study regarding diagnosis and discovery?

Answer 144

It reported a diagnostic yield of about 35%. It also identified 12 new genes that were not previously associated with developmental delay

Question 145

What is the primary aim of the PAGE project?

Answer 145

Its primary aim is to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases

Question 146

How does PAGE differ from many previous genetic association studies?

Answer 146

A key difference is its focus on ethnically-diverse population-based studies, in contrast to previous studies often limited to populations of European descent and a single phenotype

Question 147

What is the main goal of the ENCODE project?

Answer 147

he main goal is to build a comprehensive catalogue of candidate functional elements in the genome. This includes genes (protein-coding and non-protein coding), transcribed regions, and regulatory elements, along with information about the tissues, cell types, and conditions where they are active

Question 148

What types of methods do ENCODE investigators use to identify functional elements?

Answer 148

For gene elements, methods include sequencing diverse RNA sources, comparative genomics, bioinformatics, and human curation. For regulatory elements, methods include DNA hypersensitivity assays, DNA methylation assays, and immunoprecipitation of proteins that interact with DNA and RNA, followed by sequencing