Genetics MOHD unit 2

Autosomal dominant polycystic kidney disease

1:1,000 most common potentially lethal single-gene disorder. 8-10% of all end-stage renal disease. Autosomal dominant inheritance (males and females affected equally)

Vertical inheritance - multiple generations - 50% chance of transmitting the mutant allele

15% of cases are de novo

Multiple bilateral renal cysts

extrarenal cysts

Intracranial aneurysms

Mitral valve prolapse

Multiple bilateral renal cysts (ADPKD)

Kidney enlargement, UTI, nephrolithiasis pain, hematouria, hypertension

End stage renal disease

Extrarenal cysts

Mostly on the liver

pancreas

seminal vesicles

most are asymptomatic

Autosomal dominant inheritance

Incompletely dominant

.25 AA severely affected

.5 Aa affected

.25 aa unaffecte

if embryonic lethal then 2/3 Aa affected and 1/3 aa unaffected

Risk assessment

1st degree - .5 parent to child/siblings

2nd degree - .25 aunt/uncle→niece/nephew, grandparent to grandchild, half-siblings

3rd degree - .125 —> great-grandparents to great-grandchildren, first cousins

ADPKD genes

Multiple genes can result in same clinical phenotypel\

PKD1 - 78% —>polycystin1 - (more severe, early age of onset 55 y/o)

PKD2 - 15% —→ polycystin 2 - (later onset, 80 y/o)

IFT140

GANAB

DNAJB11

ALG5

ALG9

Sanger Sequencing

Uses primer with flourescent nucelotide tags at the end

Specific assay design for each region sequenced

expensive

does not detect large deletions/duplications

Next-gen sequencing

Fragment genomic DNA and select targets of interest

generate short reads — usually used for whole exome seq

can detct some intragenic deletions/duplications

Testing for ADPKD

NGS of multiple genes would be the quickest and most cost-effective

Cascade testing

24 y/o brother (50% risk) is tested and negative

27 y/o sister (50% risk) ultrasound → no renal cysts, so do you predict her risk

what about testing affected individuals daughter

Bayesian analysis

The probability of A happening given B already happened For individuals @ 50% risk for ADPKD clinical dx made if >or= 3 cysts are present from 15-39 y/o

Predictive genetic testing in children

We should not test kids for adult onset disorders

Takes away their autonomy of wanting to know their dx

Autosomal dominant disorders

Neurofibromatosis type 1 (NF1)

Marfan syndrome

Achondroplasia

NF1

1:3000

cafe-au-lait — tan spots

Neurofibromas (cutaneous, plexiform)

Lisch nodules, optic pathway glioma

macrocephaly, learning problems

NF1 gene encodes neurofibromin

Tumor suppressor gene

50% de-novo/50% inherited

can be mosaic (harder to diagnose, should probably get testing from abnormal spots)

Marfan syndrome

1:5,000-10,000

Aortic dilation/dissection

Mitral valve prolapse

Ectopia lentis/ high myopia

Tall stature with long limbs, chest deformity, scoliosis, arachnodactyly

FBN1- encodes fibrillin-1

Extracellular matrix protein

25% de novo, 75% inerited

Variable expressivity

Affected individuals with the same genotype have different manifestations of disease

Allelic heterogeneity

Multiple difference pathogenic variants (alleles) can cause the same phenotype (NF1, Marfans)

Achondroplasia

1:26,000: Most common skeletal dysplasia

Disproportionate short stature 4’1’’ women 4’4’’ men

Rhizomelic limb shortening

Narrow craniocervical junction 7.5% of risk without correction

motor delays, normal intellect

FGFR3 p.Gly380Arg

encodes GFR 3

no allelic heterogenity

80% de novo, 20% inherited

Paternal age effect

Homozygous is lethal

Autosomal recessive polycystic kidney disease (ARPKD)

1:10,000-40,000

Enlarged echogenic kidneys - 30% mortality in 1st yr due to pulmonary hypoplasia

50% progress to ESRD

50% liver involvement

75% have biallelic pathogenic variants in PKHD1

encodes fibrocystin, interacts with polycystin 1 and polycystin 2

Autosomal recessive inheritance

Horizontal inheritance - same generation

Consanguinity increases the risk of autosomal recessive disorders

homozygous pathogenic variant is inherited from a common ancestor

Autosomal recessive risk assessment

using her new risk after testing —→ .12%

This individual has a nonsense mutation that results in a loss of function

Other variants:

Pathogenic/likely

Benign/likely

Variant of uncertain significance

What is the probabiliyt the sister has ADPKD given she has no renal cysts at age 25

50/50 chance as she is a first degree relative

false negative - 5/100 chance of negative ultrasound but has ADPKD

negative ultrasound given she has no ADPKD - 1 chance

joint probability

just under 5% —- not actually 50%

unaffected sibling carrier risk is 2/3 bc aa is fully affected

pseudodominance

disease appears to be vertically transmitted with 50% risk - when 1 carrier and 1 affected