medical genetics in pediatrics - pediatrics genetics 2019.pdf · • mosaicism in 2% of cases...

Medical genetics in pediatrics

Kálmán Tory

Semmelweis University, Ist Department of Pediatrics

Key points

• The human genome

• Classification of the genetic disorders in the clinical practice

• How to identify the causal mutation in a monogenic disorder?

250M

2012 1203 1040 718 849 1002 866 659 785 745 1258 1003 318

200M 191M181M

171M159M

146M141M

48M 51M

601 562 805 1158 268 1399 533 278 522 905 96 13

155M

59M

0,017M

Number of bases per

chromosome:

Number of protein-

coding genes:

135M 135M 134M115M

107M102M

90M81M 78M

59M 63M

The 3.3 billion bases and the 20.000 genes of the nuclear genome

~3,5 Gb~23.000

~0,14 Gb~14.000

250M

2012 1203 1040 718 849 1002 866 659 785 745 1258 1003 318

200M 191M181M

171M159M

146M141M

48M 51M

601 562 805 1158 268 1399 533 278 522 905 96 13

155M

59M

0,017M

Number of bases per

chromosome:

Number of protein-

coding genes:

135M 135M 134M115M

107M102M

90M81M 78M

59M 63M

The 3.3 billion bases and the 20.000 genes of the nuclear genome

250M

2012 1203 1040 718 849 1002 866 659 785 745 1258 1003 318

200M 191M181M

171M159M

146M141M

48M 51M

601 562 805 1158 268 1399 533 278 522 905 96 13

155M

59M

0,017M

Number of bases per

chromosome:

Number of protein-

coding genes:

135M 135M 134M115M

107M102M

90M81M 78M

59M 63M

The mitochondrial genome is tiny as compared to the nuclear one

Which genome has a higher density of protein-coding genes?

1. the nuclear (100x).


3. the mitochondrial (10x).

4. the mitochondial (100x).

Which genome has a higher density of protein-coding genes?



3. the mitochondrial (10x).

4. the mitochondial (100x).

nuclear: 20 000 genes / 3 300 000 000 bases = 6 genes / Mb

mitochondrial: 13 genes / 17 000 bases = 760 genes / Mb

Key points




Types of genetic disorders

I. Nuclear genome (3G bases, 23 chromosomes, 20 thousand genes)

1. Chromosomal abnormalities

2. Monogenic disorders

3. Oligo- and polygenic diseases

II. Mitochondrial genome (17k bases, 37 genes)







Different: patomechanism

methods of investigation

recurrence risk

Chromosomal abnormalities= alterations of the copy number

Numerical Structural (Copy number variations)

Numerical chromosomal abnormalities

First genetic disorders with an identified origin (1958-1960)

1. Prevalence

– >50% of spontaneous miscarriages

– 0.6% in newborns

2. Method: karyogram

3. Pathomechanism

Miko, I. (2008) Mitosis, meiosis, and inheritance. Nature Education 1(1):206

http://cai.md.chula.ac.th/lesson/down_syndrome/contents/q08a.htm#Familial

3. Translocation with an elevated recurrence risk (≤10%)

http://cai.md.chula.ac.th/lesson/down_syndrome/contents/q08a.htm

The recurrence risk in numerical abnormalities

If the parents are not translocation carriers, the recurrence risk is:

2-4x higher than in the general population, but still <1-2%!

The typical pedigree in a chromosomal abnormality

= sporadic occurence

Numerical chromosomal abnormalitiesthat are compatible with extrauterine life

– Autosomal:

• Down (47,XX/XY, +21 )

• Edwards (47,XX/XY, +18)

• Patau (47,XX/XY, +13)

– Sex chromosomes

• Turner (45,X)

• Klinefelter (47,XXY)

• …

Down syndrome

• 47,XX/XY, +21

• often results in spontaneous miscarriage

• Incidence in newborns: 1:800

• life expectancy is ~50 years

• the region responsible for most of thephenotypic features is the 21q22 locus

Origin of trisomy 21

• meiotic non-dysjunction in 95%,

• translocation in 3%,

• mosaicism in 2% of cases

Typically has a maternal origin:

Rare autosomal trisomies

Patau syndrome

47,XX/XY, +13

cleft lip and palate

polydactyly

microphthalmia

Edwards syndrome

47,XX/XY, +18

overlapping fingers

microcephaly

prominent occiput

micrognathia

result from meiotic non-dysjunction in 90% of cases

leads to in utero death in 95% of cases

incidence at birth: ~1:5-10.000

life expectancy: few days – few weeks

cardiac abnormalities > 90%

severe developmental delay, renal disorder

Turner syndrome

• 45, X (mosaicism in 20%!)

• paternal origin in 80% (!)

• no relationship with maternal age

• causes in utero death in 98%

(15% of spontaneous miscarriages)

• incidence in newborns: 1:2.000

• short stature – haploinsufficiency of the SHOX gene

Why X monosomy is pathogenic?

1. there are mutations on the single X chromosome

2. some genes cannot be transcribed from both chromosomes

3. the two X chromosomes cannot recombine

4. as the single X is inactivated in some cells, no X remains active

Turner syndrome primarily results from the shortage of the

‘pseudoautosomal regions’ that are expressed from both sex chromosomes

Structural chromosome abnormalitiescopy number variations (CNV)

• CNVs: deletions, duplications (>1 kb)

• partly result from unequal recombinations during meiosis

1. copy number polymorphisms (CNP), small, typically <10kb

– 0.4% of the genome is different in CNPs between two individuals

(> single nucleotid polymorphisms!)

2. microdeletions and duplications (5MB - few 100kb)

– rare, a large CNV (>1 Mb) is found in only 1% of the population

– often pathogenic: enriched in patients with developmental delay, autism,

schizophrenia

• Rarely by karyogram (bad resolution)

(>4-10Mb!)

• Fluorescent in situ hybridization

(FISH, >200kb, better resolution, but targeted)

• Semiquantitave PCR-based methods

(high resolution, targeted)

• Comparative genomic hybridization

(CGH, >1kb), whole genome, high resolution

B (B )

QMP S F elektroferog ramja

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pozitív (het. deletált)

negatív kontroll

vakvízA B

A Øheterozigótaság elvesztése

B (B )


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A B

A Øheterozigótaság elvesztése cycles fragment length

control

het del.

Detection of CNVs

typically dominant

recessive

Pathogenicity of a CNV

How to know whether a CNV is pathogenic or benign?

1. known CNP?

2. appeared de novo? (1/40 newborns carry a de novo CNV)

3. size? (>1 Mb is often pathogenic)

4. is there a known associated disease?

When to suggest a microdeletion syndrome?

Role of parental imprinting in the pathogenicity

Angelman syndrome

severe intellectual deficiency, inappropriate laughter, epilepsy

Prader-Willi syndrome

developmental delay, obesity, hypogonadism

deletion of 15q11-q13 (FISH)

Role of parental imprinting in the pathogenicity

Angelman syndrome

severe intellectual deficiency, inappropriate laughter, epilepsy

Prader-Willi syndrome

developmental delay, obesity, hypogonadism

deletion of 15q11-q13 (FISH)

Maternally inherited chr15 (UBE3A gene) Paternally inherited chr 15

Role of parental imprinting...

Liger (the largest big cat) Tigon

father: lion, mother: tiger father: tiger, mother: lion







Typically result from single or

few nucleotide-alterations

1.5% of the genome is the coding region

normal sequence

A T G C G A T T A G A G T A C A T A A C G G G G

Met Arg Leu Glu Tyr Ile Thr Gly

silent polymorphism

A T G C G A T T G G A G T A C A T A A C G G G G


non-silent polymorphism / missense variant

A T G C G A T T C G A G T A C A T A A C G G G G

Met Arg Phe Glu Tyr Ile Thr Gly

nonsense mutation (premature stop codon)

A T G C G A T T A G A G T A A

Met Arg Leu Glu STOP

Types of variants

normal sequence



in-frame deletion (involving 3 bases or its multiple)



A T G C G A T T A T A C A T A A C G G G G

Met Arg Leu Tyr Ile Thr Gly

Out of frame deletion (number of inserted nucleotides is not divisible by three)



A T G C G A T T A A G T A C A T A A C G G G G A

Met Arg Leu Ser Thr STOP

Types of variants

Typical differences in the coding sequencebetween an individual and the human reference genome

Mutation

• hundreds coding / individual

• appeared more recently in the human evolution

• might be pathogenic in monogenic disorders

SNP

• 20.000 coding / individual

• appeared >several 10k years ago in the human evolution

• undergone evolutionary selection

allele frequency = 1% <<

Mutations and polymorphisms

Methods

Sanger sequencing Next-generation sequencing largescale – even whole exome or genome

Diseases with an identified molecular basis

37 34 30 34 3660 60 51 47

84

56 49

8869 64

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128122

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130124146

195

160

335

246266

252242224

0

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400

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16

∑ > 5400 (2019.09.)

Human Genome Project

Exom-sequencing

Monogenic diseases

• result from defects in a single gene

• affect 1-2% of the general population

• responsible for 20% of infant mortality and 10% of pediatric inpatient care

• typically result from mutations (role of polymorphisms is exceptional)

• inherited in a Mendelian fashion:

– if one deleterious allele is enough to be pathogenic: dominant

– if both required: recessive transmission

recessive disease ≠ homozygous mutation

compound heterozygous

(the two mutations are different)

homozygous

(mutations of the two alleles are the same)

AR disorders may develop if the parents carry mutations in the same gene

Typical family pedigrees in autosomal recessive disorders

- the family history is often negative

- consanguinity (or inbred populations) are risk factors

compound heterozygous

(the two mutations are different)

homozygous

(mutations of the two alleles are the same)

AR disorders may develop if the parents carry mutations in the same gene

Typical family pedigrees in autosomal recessive disorders

Congenital nephrotic syndrome

• Two-weeks old newborn

• NPHS1:

– c.1048T>C , heterozygous p.S350P

– c.468C>G , heterozygous, p.Y156*

Autosomal recessive disorders

• >1700 disease / trait

• typical transmission in severe childhood disorders

• cystic fibrosis, enzymopathies / inborn errors of metabolism, storage

disorders, steroid-resistant nephrotic syndrome, nephronophthisis and the

vast majority of ciliopathies, congenital hepatic fibrosis…

Autosomal dominant transmission

• 4500 AD disease / trait

• How can a single deleterious allele be pathogenic?

– haploinsufficiency (~deletions of chromosomal regions)

– gain of function (Huntington, amyloidosis)

– dominant negative effect (osteogenesis imperfecta)

– second somatic mutation (ADPKD)

50% is not enough

somatic mutation of the

normal allele results in

clonal proliferation

the abnormal protein is

damaging for the cell

the abnormal

protein is damaging

for the polimer

Offspring of affected individuals have

a 50% risk of being affected


Is this pedigree compatible with an AD

inheritance?

De novo mutations

• All children inherit 50-100 de novo mutations (!)

• 1-2% of them are located in the coding regions

• thus, children in general carry ~1 de novo exonic mutation

• most of the de novo mutations have a paternal origin

– spermatogenesis necessitates 20-25 mitotic divisions per year

– oogenesis necessitates 20-30 mitotic divisons in total

• paternal age correlates with the number of de novo mutations

X-linked inheritance

• X-linked recessive • X-linked dominant

Males are more severely affected in both cases

Females and males are unequally affected

Duchenne, Alport,

haemophilia A, B

hypophosphatemic rickets

Oligogenic inheritance

Bardet-Biedl syndrome

Katsanis et al.: Science,

2001;293:2256-9

Oligogenic inheritance

Mutation of a second gene explains the incomplete penetranceKatsanis et al.: Science,

2001;293:2256-9

Polygenic diseases

• often multifactorial disease, with genetic components, modified by the polymorphisms / mutations of several genes

• familiar clustering of these disorders is much less important than in monogenic diseases, often appear as sporadic cases

• congenital heart defect, non-syndromic cleft lip and palate, hypospadias, neural tubedefects

• neurodevelopmental deficiencies (autism, learning difficulties, schizophrenia) wereconsidered to polygenic – they have been found to result from de novo CNVs / pointmutations

Polygenic inheritance

recurrence risk in a first-degree

relative: 5-10%

UKNat Gen, 2009

n=2361

control = 4818

20q13

16q22

7q31

North-AmericaNat Gen, 2009

n=3426

control=11963

16p11

22q12

10q22

2q37

19q13

Polygenic diseases – ulcerative colitis, Crohn’s

Which loci are implicated in the pathogenesis?

JapanNat Gen, 2009

n=1384

control=3057

13q12

1q23

7q31

Mitochondrial inheritance

There are ~1500 mitochondrial proteins. Most of them are encoded by the nuclear genome!

Mitochondrial DNA is inherited maternally.

Each cell contains thousands of copies of mitochondrial DNA. A mutation may affect only part of

the mitochondrial DNA (‘heteroplasmy’) or may affect all (‘homoplasmy’).

The difficulty of risk prediction: the mitochondrial genetic bottleneck

random shift of mtDNA mutational load between generationsTransfer of small number of mt DNA

Is it possible to be heterozygous for a mitochondrial mutation?

1. Yes, if one of the two mitochondrial DNA copies contains the

mutation.

2. No, all mitochondrial DNA copies are identical.

3. No. Though the sequence of the mitochondrial DNA copies can be

different, there are several copies, not only two, so it is not possible to

be heterozygous for a mitochondrial mutation.

4. Yes, if approximately half of the DNA copies contain the mutation.

Key points




Why is it important to know which gene

is responsible for a disorder?

• Identification of the mutation confirms the clinical diagnosis

• helps to determine the recurrence risk for the affected families

• allows studying the pathomechanism

• might already influence the therapy

• Autosomal recessive disorders • Numerical chromosome abnormalities

• De novo single nucleotide mutation • Deleterious copy number variations

In severe diseases, the family history is often negative

What is important in the family history?

• Potential consanguinity? Where are the parents from? Do theyoriginate from the same small population? (suggestive of homozygousmutations in recessive disorders)

• Maternal age? (numerical chromosome abnormalities)

• Paternal age? (de novo point mutations)

Phenotype

informative not informative

phenotype suggestive

of CNVs

malformation

CGH array

phenotype suggestive of

a monogenic disorder

exome sequencing

Filter: Ø

No characteristic phenotype, but a monogenic origin is

suggested, let us sequence the exome…

Filter: polymorphisms excluded (frequent variants are unexpected to cause rare diseases)



Filter: polymorphisms and previously found variants excluded



Turnpenny, Ellard: Emery's

Elements of Medical Genetics

Filter: polymorphisms, previously found variants, intronic, intergenic and silent variants excluded



• Allele frequency

• Evolutionary conservation

• Amino acid change

Rodriguez G et al. Circ Cardiovasc Genet. 2011;4:349-358

How to select the potentially pathogenic missense variants?

• Allele frequency

• Evolutionary conservation

• Amino acid change

How to select the potentially pathogenic missense variants?

Filter: keeping only mutations that are predicted to be pathogenic



Filter: as the parents are consanguineous, only HOMOZYGOUS mutations predicted to be pathogenic are kept



The causal mutations in a monogenic disorder are typically:

• rare in the general population (allele frequency < 0.1%)

• lead to truncation of the protein or affect evolutionary conserved amino acids

• segregate with the disease in the family wtǀQ2158Xwtǀwt

wtǀwtwtǀQ2158X

wtǀQ2158X

Despite all precautions, not every mutations,

published as causal, are pathogenic...

New Engl J Med, 2010Slide from Stanislas Lyonnet

SH3TC2

New Engl J Med, 2010

174 HGMD

159 „surely pathogenic”

21 monogenic disease

- 16 heterozygous

- 4 homozygous

- 1 hemizygous

ABCD1

Once we identified the causal mutation, it is easy to test unaffected family members, but it may raise ethical problems

Even parents are not allowed to ask for presymptomatic testing of

their offspring if no treatment is available for the disease

Identification of the

causal gene

animal

model

subcellular localization of the

encoded protein

protein-interactions

signaling pathways

organ-specific

expression

genotype-phenotype correlations

Identification of causal genes is a milestone in the understanding of the pathomechanism

Gallagher et al: Molecular Advances

in ADPKD, Chronic Kidney Disease,

Volume 17: 118-30

Cystic kidney disorders are secondary to mutations of genes encoding primary cilium proteins

The mitotic angles of renal tubular cells are altered in rats with polycystic kidney

Fischer et al.: Defective planar cell polarity in polycystic kidney disease. Nat Genet. 2006

normal lengthening of a

renal tubule is due to

mitotic divisions

the altered mitotic divisions

lead to cyst formation

Simons M, Walz G: Polycystic kidney disease: Cell division without a c(l)ue?

Kidney International 2006

The mitotic angles of renal tubular cells are altered in polycystic kidney disease

Summary

• The human genome currently does not really explain the differences

between humans and animals.

• The methods of investigation have undergone a revolutionary

development during the last two decades.

• If we cannot establish a clinical diagnosis, it can be still very difficult

to identify the genetic cause in monogenic diseases.

Recurrence risk in polygenic disorders

• Difficult to determine

• If several family members are affected, it may be mono- or oligogenic

• A rough estimation:

The risk in first-degree relatives is the square root of the prevalence in the general population

Szteroid-rezisztens nephrosis szindróma

Újszülöttkori diabetes mellitus(kezdet: <6 hó, 1:100.000-500.000)

Permanens

(50%)

Tranziens

(50%)

KCNJ11 (Kir6.2)

35-50%

ABCC8 (SUR1)

~7%

Brinkman et al. Nature Reviews Genetics 2006

ABCC8 (SUR1)

~15%

aktiváló, gain-of-function mutációk

Akut lymphoid leukemia

Jó prognózis

• t(1,19) (5%)

• t(12,21) (20-25%)

• hyperdiploid

Rossz prognózis

• t(9,22) (Ph+) (3-4%)

• t(4,11) (5%)

• hypodiploid

A leggyakoribb gyermekkori malignitás.

Ross et al. Blood 2003;102:2951-9

Nagyon magas rizikó

5 éves túlélés: 46%

Alacsony rizikó

5 éves túlélés: ~90%

Neuroblastoma

A 3. leggyakoribb gyermekkori malignitás.

Az N-myc gén 50-400x amplifikációja a

neuroblastomák 25-30%-ában található meg.

Rossz prognózissal társul:

Stage I vagy II neuroblastomában a teljes túlélés az

N-myc gén-amplfikáció függvényében: 72 vs. 90%

(n = 2660)

Mikor nem szabad genetikai vizsgálatot végezni?

1. Tünetmentes kiskorú genetikai vizsgálata nem engedélyezett (a szülők

kérésére sem), ha a gyermeknek nem származik előnye a diagnózis

ismeretéből.

2. Ki szeretné ismerni milyen mutációkat hordoz?

Az egy- és kétgyermekes szülők többsége nem tudja, hogy születhetett volna beteg gyermekük!

9/16 potenciálisan beteg gyermeket nemző kétgyermekes szülőpár nem tudja,

hogy a gyermeke beteg lehetett volna

Terápiás lehetőségek

Liu X L et al. JASN

2004;15:1731-1738

2004 by American

Society of Nephrology

wild type

nephrin

nephrin

actin HEK293

cells

Mutáció-specifikus kezelés az NPHS1 mutációt hordozó betegben

500mg Na 4-phenylbutyrate/day

Patomechanism

Összefoglalás - módszertan

Összefoglalás

• A vizsgáló módszerek fejlődésének köszönhetően egyre több betegség genetikai hátterét ismerjük meg.

• Ez döntő a betegségek patomechanizmusának megismerésében, oki terápia kifejlesztésében.

• A közeljövőben már nem a genetikai eltérés azonosítása lesz kihívás, hanem annak eldöntése, hogy mi patogén és mi nem.

• A genetikai vizsgálatok indikációját alaposan meg kell fontolni. Nem kell mindent tudjunk.

Van ~23.000 génünk, sok ezer betegség

Honnan lehet tudni, hogy egy betegségért melyik gén felelős?


Egy családban két beteg és két egészséges gyermek van.

A betegek tünetei megfelelnek az ARPKD tüneteinek, tudjuk

tehát, hogy recesszíven öröklődik.

De tegyük fel, hogy a génje nem.


Statisztikailag a genom ¼-e felel meg ennek az eloszlásnak.


Ennek a megoszlásnak – statisztikailag - a genom ¼ * ¾ * ¾ = 9/64-ed része felel meg.

3.000 Mb x 9/64 = 420 Mb (még mindig óriási terület)

Az ARPKD locusa: 6p21

Zerres K et al.: Mapping of the

gene for autosomal recessive

polycystic kidney disease

(ARPKD) to chromosome

6p21-cen.

Nat Genet. 1994 7:429-32

De: a lehetséges gének száma ~100

A PKHD1 identifikálásaWard CJ et al.: The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet. 2002, 30:259-69.

A PKHD1 által kódolt fehérje, a polyductin

Sok más cisztás

vesebetegségben mutáns

proteinhez, a polyductin is

csillófehérje

Szerkezete egy

receptoréra emlékeztet

Az MKS3 allélok és a fenotípus közötti kapcsolat

1. allél

2. allél0

1

vad típus

hypomorph

funkcióvesztett

MKS3 allél

De egy gén nem csak egy betegséget okozhat!

Ugyanazt a betegséget több gén mutációja is okozhatja (genetikai heterogenitás),és egy gén több betegséget is okozhat – monogénes betegségekben is!

PKD1

wtǀQ2158Xwtǀwt

wtǀQ2158XwtǀQ2158X

wtǀQ2158X

25 yrs: neg. US

Rossetti S et al., Kidney Int, 2009 Vujic M et al., JASN, 2010

PKD1

wtǀR220WR3277Cǀwt

R3277CǀR220W

Dg: In utero

Újszülött: Resp. insuff.

8 yrs: cisztás vese

R3277CǀR220W

Dg: In utero

Újszülött: Resp. insuff.

1 yr: cisztás vese

41 yrs: neg. US 34 yrs: neg. US

Ugyanazon gén különbözői mutációi eltérően öröklődhetnek... ADPKD recesszív öröklésmenettel?!

Domináns öröklésmenet Recesszív öröklésmenet

wtǀwt

Miért különbözünk egymástól?

Jelentős részben a Single Nucleotid Polimorfizmusoknak (SNP)

köszönhetően:

>18 millió SNP ismert (a

(a 3,3 milliárd bázisból)

minden 150-200. bázis egy SNP

1. ember

2. ember

3. ember

A cisztás vesebetegségeket csillófehérjéket kódoló gének mutációi okozzák

All offspring of a 21q21q translocation carrier are affected by Down syndrome

http://cai.md.chula.ac.th/lesson/down_syndrome/contents/q08a.htm#Familial

3. Translocation

http://cai.md.chula.ac.th/lesson/down_syndrome/contents/q08a.htm

Human Genom Project

• nuclear genome sequence in 9 individuals (8 men)

• human genome consists of 3,3 milliárd bázisból áll

• ~3 billion $

Frytillaria assyriaca

Miért nem szekvenálunk exomot mindenkinél?

• Ez a jövő...

• De: több ezer variánst, több tucat mutációt találunk mindenkinél

• Melyik a patogén?

• Lehet egyszerű a választás (a fenotípus ismeretében), de előfordulhat, hogy heteket kell tölteni az analízisével

A rendelkezésre álló módszerek

Domináns vagy recesszív betegség az ADPKD?

Miért lesz neonatalis az ADPKD? Negatív anamnézisű családban

neonatalis ADPKD?

PKD1

wtǀQ2158*wtǀwt

wtǀQ2158*wtǀQ2158*R3277Cǀwt

R3277C ǀ Q2158*

ESRD: 43 yrs

Dg.: 15 yrs

CRF: 44 yrs

25 yrs: neg. US

Dg.: in

utero

CRF: 17 yrs

Rossetti S et al., Kidney Int, 2009 Vujic M et al., JASN, 2010

PKD1

Dg: In utero

Neonate: Resp. insuff.

8 yrs: cystic kidney

Dg: In utero

Neonate: Resp. insuff.

1 yr: cystic kidney

41 yrs: neg. US 34 yrs: neg. US

Offspring of affected individuals have

a 50% risk of being affected

Is this pedigree compatible with an AD

inheritance?


AR transmission – risk calculation

~100%

probability of being carrier

probability of being affected50%

⅔ 2pq

⅔ x 2pq x 0,25 = 0,7% for the nephew to be affected

cystic fibrosis: prevalence: q2=1/2500, q=1/50=2%, p=98%,

frequency of carriers in the general population: 2pq ~ 4%

medical genetics in pediatrics - pediatrics genetics 2019.pdf · • mosaicism in 2% of cases...

Documents