ClinGen exam 1

proportion of genes shared by 1st degree relatives

1/2

proportion of genes shared by 2nd degree relatives

1/4

proportion of genes shared by 3rd degree relatives

1/8

first degree relatives

siblings, dizygotic twins, parents, children

second degree relatives

half siblings, uncles/aunts, nephews/nieces, double first cousins

third degree relatives

first cousins, half uncles/aunts, half nephews/nieces

fourth degree relatives

first cousins once removed

fifth degree relatives

second cousins

sixth degree relatives

second cousins once removed

allelic heterogeneity

different allelic combinations may have somewhat different clinical consequences

cystic fibrosis

common AR condition, lots of clinical variability → many different clinical presentations based on different allelic combinations (lungs, pancreas, GI tract, liver, fertility), modulator therapies have now become available

• example of allelic heterogeneity

locus heterogeneity

multiple gene alterations can cause the same disease — mostly seen with dominant conditions, but can be seen with recessive conditions too

Noonan syndrome

AD RASopathy caused by variants in PTPN11, SOS1, KRAS, RAF1, BRAF, and MEK1 (MAP2K1 genes), leads to distinctive appearance (short stature, broad or webbed neck), symptoms include heart defects/differences in coagulation/variable developmental delay

• example of locus heterogeneity

clinical heterogeneity

pathogenic variants in the same gene can cause different phenotypes

LaminA/C

Pathogenic variants in lamin A/C gene cause a broad range of clinical syndromes that show tissue-restricted abnormalities of post mitotic tissues, such as muscle, nerve, heart, and adipose tissue

• example of clinical heterogeneity

Pedigree patterns to look for to determine inheritance patterns

transmission, sex differences, segregation

AR inheritance

Trait only expressed in homozygotes or compound heterozygotes

If both parents are unaffected but carriers, have 1 in 4 chance (25%) of passing deleterious variants to any offspring

Same frequency in XX and XY individuals

De novo variants are very unlikely

Likelihood of condition occurring is increased with inbreeding and consanguinity

Tay-Sachs disease

AR condition

Lysosomal storage disease, typical onset between 3-6 months of age and lifespan typically doesn’t exceed 4 years

Cherry red spot seen on ophthalmologic exam (in retina) → storage of substances that can’t be broken down in Tay Sachs

Begins with progressive weakness, loss of motor skills, decreased attentiveness, and increased startle response; progresses to seizures, blindness, spasticity

Individuals of Ashkenazi Jewish, Cajun, Amish French Canadian, and possibly Irish descent at increased risk to be carriers

Most affected children are non-Jewish as screening is not always routinely offered

Loss of function condition, loss/inactivation of HEXA causes toxic buildup of GM2 (ganglioside in central/nervous systems) and leads to cell death

50% function is sufficient, carriers are healthy

hereditary hemochromatosis

AR condition

Most common monogenic condition in the US (1/250 Americans affected)

Increased intestinal absorption of iron, when menstrual stops is when many people who menstruate see symptoms (symptoms show up in 20s typically for people who don’t menstruate)

Deposition of iron into organs, and iron levels are reduced by blood loss (treated with phlebotomy)

Not all AR conditions are rare

AD inheritance

Affected individuals in every generation (vertical transmission)

Child of affected parent at 50% risk

Same frequency in XX and XY

Significant proportion of isolated cases due to de novo variants (the less the fitness, the greater the proportion due to new variants

Marfan syndrome

AD condition

Condition of the connective tissue

1/5000 individuals affected

75% of affected individuals inherit the condition from a parent

Loss of function (dominant negative), mutant product is produced from one allele and mutant protein interferes with function of the protein produced by the normal allele

achondroplasia

AD condition

Most common cause of short stature (1/20,000-30,000 live births)

Fully penetrant (guaranteed to develop condition if you have a variant in FGFR3)

Association with advanced sperm age (advanced paternal age) → associated with greater chance of de novo variants, typically over age 45

Children who inherit two pathogenic variants are more severely affected/lethal (example of a double dominant, homozygous for dominant allele → rare, most of the time people with two copies won’t survive for most conditions)

Gain of function condition - FGFR3 usually inhibits chondrocyte proliferation when activated, but achondroplasia is FGFR3 activation without binding of the ligand → GoF causes protein product to gain a new function

familial hypercholesterolemia

AD condition

One copy of pathogenic variant in LDLR leads to somewhat elevated risk of heart disease (milder presentation in carriers)

2 pathogenic alleles of LDLR causes very elevated cholesterol levels and early arteriosclerosis with visible deposits of cholesterol in skin, eyelids, and cornea

Still considered AD because you still see an effect with one non-working copy

Half of normal product is insufficient for normal function (example of loss of function, incomplete dominance)

X-linked recessive inheritance

More males than females affected

Heterozygous females are usually unaffected (although this is shifting a bit, person may have mild manifestations of condition)

All daughters of an affected man are obligate carriers

Sons of a heterozygous mother have a 50% chance of being affected

No father to son transmission

Affected males often related through females

Significant proportion of isolated cases are due to a de novo variant

Duchenne Muscular Dystrophy

One of several conditions caused by mutations in the dystrophin gene

Gower sign and abnormal gait, progressive symmetrical proximal muscle weakness, progresses to cardiac involvement

Without intervention: diagnosis at 5 years, use wheelchair at 12 years, cardiomyopathy at 18 years, death in early 20s secondary to cardiomyopathy or respiratory insufficiency

Implications for carrier females (may report fatigue, muscle pain, increased frequency of dilated cardiomyopathy)

30% of cases are de novo (Haldane hypothesis → in many X-linked conditions where fitness is 0, about 30% are de novo)

• But fitness isn’t always 0 if there has been treatment

X-linked dominant inheritance

No male to male transmission

Affected males have no affected sons and all daughters are affected

All offspring of an affected individual have a 50% change of inheriting the condition

Twice as many affected females compared to affected males and typically have milder (but variable) symptoms

X-linked chondroplasia punctata

>95% of cases are XX

Skeletal: short stature, asymmetric shortening of the limbs, scoliosis

Skin: ichthyosis and hyperkeratosis

Hair: coarse, scarring alopecia

Eyes: cataracts, microphthalmia, and/or microcornea

Typical intelligence

pseudoautosomal inheritance

seen with genes in the pseudoautosomal region of the X and Y chromosomes (where chromosomes line up for recombination), only see father to son transmission

Y-chromosome infertility

characterized by azoospermia or oligozoospermia → specific area on q arm (DAZ gene) that plays a role in sperm production, variants can be passed down from father to son

mosaicism

presence of at least two cell lines that differ genetically but are derived from a single embryo

most common form of inheritance

multifactorial inheritance

polygenic inheritance model of multifactorial inheritance

assumes the actions of multiple genes, less influence from environment

threshold model of multifactorial inheritance

Closely related individuals have more genes in common, therefore affected individuals have a greater than expected number of affected relatives compared to the general population

factors increasing risk to relatives for multifactorial inheritance

closeness of relationship to proband, multiple affected family members, severe or early onset of disease, sex influence on manifestation of condition (proband of more rarely affected sex), heritability of disorder

conditions more common in XY

Clubfoot (2:1)

Pyloric stenosis (5:1)

Gastroschisis: (1.5:1)

Cleft lip and palate

conditions more common in XX

Congenital hip dislocation (6:1)

Neural tube defects (1.4:1)

Cleft palate

heritability

fraction of the total phenotypic variance of a quantitative trait that is due to genetic variation

• Heritability of 0: genotype contributes nothing

• Heritability of 1: genotype totally responsible for the phenotypic variance

genetic syndromes with psychiatric risk:

Prader-Willi syndrome: OCD

22q11.1 deletion: schizophrenia, depression, bipolar

Smith-Magenis syndrome: anxiety, bipolar

Williams syndrome: anxiety, ADHD

Lesch-Nyhan syndrome: OCD

Individualizing risk assessment for multifactorial inheritance for psychiatric conditions

Age of onset in affected individuals

Age of at-risk client

Sex of at-risk client

Severity and course of illness in affected individuals

Potential environmental factors in disease onset

genetic anticipation

when expansion gets longer from generation to generation (typically only from egg or sperm cell, important maternal or paternal contribution)

• Increase in severity/earlier onset of phenotype in successive generations

fragile X inheritance, anticipation, and gene

X-linked, maternal anticipation, FMR1

fragile X repeat type and thresholds

CGG

normal repeats: <44

intermediate: 45-54

premutation: 55-200 (at risk for FXTAS and FXPOI)

full mutation: 200+

fragile X features

Moderate ID seen in majority of affected males, range of ID in females due to lyonization

Autism spectrum disorder present in 50%-70% of individuals affected with Fragile X

Features in males:

• Long face, large ears

• Joint laxity (may present as clumsiness in a child)

• Mitral valve prolapse (MVP)

• Soft skin - also often seen in connective tissue disorders

• Macroorchidism (enlarged testicular volume, most obvious post-puberty)

• Macrocephaly

• Tactile defensiveness, poor eye contact, perseverative speech, limited impulse control, and distractibility

• Typical fertility

Huntington inheritance, anticipation, and gene

AD, paternal anticipation, HD (HTT)

Huntington repeat type and thresholds

CAG

normal: 26 or less

intermediate range: 27-35 (expansion possible)

increased risk (reduced penetrance range): 36-39

full penetrance range: 40+

Huntington disease features

More repeats = earlier age of onset

3 M’s:

• Movement: uncontrolled → chorea, oculomotor disturbance, motor impairment and gait disturbance, dysarthria (motor speech disorder) and dysphagia (difficulty swallowing)

  • Later in disease; bradykinesia (slowness of movement), rigidity, dystonia (involuntary contraction of muscles)

• Memory: cognitive decline → slowed thought process, forgetfulness, anosognosia (patient is unaware of their neurologic deficit or psychiatric condition)

• Mental health/mood: depression, mood swings, affective psychosis or schizophrenic psychosis

  • Caused by cerebellar atrophy

myotonic dystrophy type 1 inheritance, anticipation, and gene

AD, maternal anticipation, DMPK

myotonic dystrophy repeat type and thresholds

CTG

normal: <35

premutation: 35-49 (risk of expansion)

mild: 50-150

classic: 100-1000

congenital: >1000

myotonic dystrophy features

Mild: cataracts, mild myotonia, normal life span

Classic: muscle weakness/wasting, myotonia, cataracts, may have shortened life span

Congenital: severe hypotonia at birth, ID, often with respiratory insufficiency and early death

Difficulty releasing grasp is one of the key clinical features

Friedreich ataxia inheritance, anticipation, and gene

AR, no anticipation, FXN

Friedreich ataxia repeat type and thresholds

GAA

normal: 5-33

premutation: 34-43

borderline: 44-65

pathogenic: 65-1300

Friedreich ataxia features

Neurologic features typically onset before 25 years: progressive ataxia of gait and limbs, dysarthria, dysphagia, areflexia (complete absence of involuntary muscle reflexes)

Musculoskeletal: muscle weakness, pes cavus, scoliosis

Hypertrophic non-obstructive cardiomyopathy → heart is still working, blood flowing as it should be, but is larger than it should be and is working harder than it should be

Endocrine: type 1 diabetes

Sensory: optic atrophy, deafness, inability to feel temperature by touch

spinocerebellar ataxia inheritance and anticipation

All dominant, many have anticipation, disease severity and age of onset correlates with repeat length, most are CAG repeat expansion disorders

SCA3: Machado-Joseph disease anticipation and founder mutation gene

Most common SCA worldwide (15-25% all SCA)

Portuguese founder mutation CAG repeat expansion in ATXN3

Paternal anticipation

DRPLA - complex type features

Chorea, seizures, dementia, myoclonus – mimics Huntington’s disease CAG repeats in ATN1

conditions where ataxia is seen

Huntington disease (AD- paternal anticipation)

Fragile X tremor ataxia syndrome (XL- maternal anticipation)

Friedreich ataxia (AR)

SCA related conditions (AD)

features resulting from degeneration of motor neurons

Muscle atrophy

Fasciculation (spontaneous twitching)

Spasticity and hyperreflexia

Spinal [and] bulbar muscular atrophy (Kennedy’s disease) inheritance and repeat thresholds

Rare, example of X-linked polyglutamine expansion

Hemizygous CAG repeats in AR gene

<34 repeats: normal

35-37 repeats: reduced penetrance

>38 repeats: full penetrance

Spinal [and] bulbar muscular atrophy features

Slowly progressive muscle weakness, atrophy and fasciculations

Androgen insensitivity – gynecomastia, testicular atrophy, reduced fertility

Onset in adulthood (20s-50s); normal life expectancy

Female carriers are typically asymptomatic, but some have been reported to have muscle cramps and occasional tremor

Amyotrophic lateral sclerosis (ALS) features

Onset in later adulthood (>55y)

Mean survival: 3-5 years after onset (respiratory failure is leading cause of death)

>45% have some degree of cognitive impairment

5-27% have frontotemporal dementia

ALS inheritance

Most is autosomal dominant with variable penetrance and expressivity

90% ALS is sporadic; 10% ALS is familial

familial causes of ALS

C9orf72, SOD1, FUS

ALS and C9orf72

~40-45% familial ALS

Hexanucelotide GGGGCC repeat expansion: >60 repeats pathogenic with 25-59 repeats intermediate range

Highly variable age of onset with 100% symptomatic by age 80

Associated with FTD (frontotemporal dementia)

ALS and SOD1

~15-20% familial ALS

90% symptomatic by age 70

Not associated with FTD

ALS and FUS

4-8% familial ALS

Earlier average onset than C9orf72 and SOD1; can present as juvenile onset

muscular dystrophy

muscular wasting and weakness

heterodisomy

parent passes on one copy of each chromosome

non-disjunction in meiosis I

isodisomy

parent passes on two copies of the same/identical chromosome

non-disjunction in meiosis II

mechanisms for whole chromosome UPD

complementation (very rare), trisomic rescue (most common), monosmic rescue, mitotic error and rescue

complementation

disomic gamete and nullisomic gamete form UPD conceptus (will always be isodisomy)

trisomic rescue

disomic gamete and monosomic gamete form trisomic conceptus, is postzygotic mitosis one copy is discarded (can be either isodisomy or heterodisomy depending on which extra chromosome drops out)

*only mechanism where we can see heterodisomy

monosomic rescue

monosomic gamete and nullisomic gamete form monosomic conceptus, which then gets replicated in postzygotic mitosis (will always be isodisomy)

mitotic error and rescue

error in postzygotic mitosis causes trisomic embryo, in a subsequent mitosis extra copy is discarded

Will be isodisomy, non-duplicated copy is often the one kicked out

genomic imprinting

Some genes are preferentially expressed from a specific allele (from either only the egg or only the sperm). For these specific areas in the genome, only one gene copy is intentionally being expressed

reasons why we may see differences in clinical phenotype when something affects imprinted region being expressed

Uniparental disomy

Mutation/deletion of an imprinted region of DNA

An imprinting center mutation

chromosomes associated with imprinting

6, 7, 11, 14, 15, 20

paternal UPD chromosomes

6, 11, 14, 15, 20

maternal UPD chromosomes

7, 11, 14, 15, 20

paternal UPD 6 condition

transient neonatal diabetes

transient neonatal diabetes

Early onset diabetes between <6-18 months of age

Severe IUGR (<10th %tile)

Sometimes present:

• Macroglossia

• Umbilical and inguinal hernias

~20% of all cases are due to paternal UPD6

maternal UPD 7 condition

Russell-Silver syndrome

Russell-Silver syndrome

Clinical features include:

• prenatal and postnatal growth restriction

• triangular face

• 5th finger clinodactyly

• asymmetry limbs (50%)

• excessive sweating of infancy

• Hypoglycemia

• typical intelligence

We also see this with maternal UPD on chr 11

UPD is not a common cause of RSS, but correlation does exist

paternal UPD 11 condition

Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome

• Can be mosaic/somatic

• 20% due to UPD (isodisomy)

• 55% due to imprinting center variant (disrupts function of gene)

• Overgrowth syndrome

  • Neonatal hypoglycemia

  • Macroglossia

  • Ear creases

  • Macrosomia

  • Hemihyperplasia

  • Abdominal wall defect; omphalocele

  • Risk of Wilm’s tumor, adrenocortical carcinoma

  • Later risk of nephrocalcinosis

maternal UPD 11 condition

Russell-Silver syndrome

maternal UPD 14 condition

Temple syndrome

Temple syndrome

• Primary features:

  • IUGR

  • Small hands and feet

  • Precocious puberty

  • Developmental delay

  • Hypotonia

  • Central obesity developing with age

• 50-60% caused by maternal UPD

• Robertsonian translocations often involve chr 14

paternal UPD 14 condition

Kagami–Ogata syndrome

Kagami–Ogata syndrome

• Common features include:

  • Polyhydramnios , placentomegaly, prematurity

  • Poor growth

  • Characteristic facial differences

  • Intellectual disability

  • Coat-hanger appearance of the ribs

  • Small bell-shaped thorax / respiratory distress

  • Abdominal wall defects

maternal UPD 15 condition

Prader-Willi syndrome

Prader-Willi syndrome

• Features:

  • Hypotonia/failure to thrive in 1st year (most common presentation)

  • Intellectual disability

  • Hyperphagia (pathological overeating)

  • Hypogonadism

• Caused by loss of expression of paternally expressed genes in 15q11-13

• 1/15,000

• Chromosome: 15q11-13

paternal UPD 15 condition

Angelman syndrome

Angelman syndrome

• Features:

  • severe intellectual disability

  • Hypotonia

  • movement disorder (ataxia)

  • seizures

• Caused by loss of expression of maternally expressed genes in 15q11-13

• 1/12-20,000

maternal UPD 20 condition

Mulchandani-Bhoj-Conlin syndrome

Mulchandani-Bhoj-Conlin syndrome

• Maternal UPD chromosome 20q11-13

• One report – 8 patients (2016)

  • Prenatal growth restriction

  • Severe short stature with proportional head circumference

  • Profound feeding difficulty-gastric tubes in most

• Two patients had initially been diagnosed with Silver-Russell syndrome

• VERY RARE

paternal UPD 20 condition

pseudohypoparathyroidism type 1b

Pseudohypoparathyroidism type 1b

Characterized by resistance to parathyroid hormone in kidneys and presents as hypocalcemia, hyperphosphatemia, and abnormally high parathyroid hormone levels.

VERY RARE

when to consider UPD testing

• Suspicious clinical findings on physical exam or prenatal ultrasound

• Molecular investigation of a condition that does not follow a typical Mendelian inheritance pattern including AR and XL

• Identification of chromosomal difference

types of structural chromosome differences

Translocations (Reciprocal and Robertsonian)

Deletions

Duplications

Inversions

Ring chromosomes

Marker chromosomes

balanced rearrangment

correct amount of chromosomes

Generally normal phenotype (unless important gene is disrupted)

1/500 frequency