Neurofibromatosis Type 1 (NF1) - PowerPoint Presentation

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NeurofibromatosisType 1 (NF1)Von Recklinghausen Disease

By: Dr.

Mahmoud

Almutadares

, House officer at KAU, MBBS

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ObjectivesEpidemiology of NF1Neurofibromin geneClinical features of NF1

Molecular basis of NF1

Gene strategies to identify modifier genes

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EpidemiologyBirth incidence: 1:2500Prevalence of 1:4000

Autosomal

Dominant with variable expression

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Neurofibromin 1Located in 17q11.2Approximately 350kb and contains 61

exons

A tumor suppressor gene.

Encodes for Neurofibromin

Over 300 different mutations reported worldwide

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Clinical FeaturesShort staturedCafé-au-lait

(CAL) spots

Freckling

Lisch

Nodules

Neurofibromas

Optic

gliomas

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Café-au-

lait

Freckles

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Plexiform

Neurofibroma

Dermal Neurofibromas

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Optic

Glioma

Lisch

Nodules

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Distinctive osseous lesion such as sphenoid dysplasia or cortical thinning of long bones

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ExpressivityExpressivity is the variations in a phenotype among individuals carrying a particular genotype, it is analogous to the severity of a condition in clinical medicine.

Variable expressivity

occurs when a phenotype is expressed to a different degree among individuals with the same genotype.

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Molecular basis of NF1

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5-10%

>90%

Large 17q11 deletions

More sever phenotype

Intragenic

Mutations

No clear-cut allele-phenotype correlations

3-bp frame deletion (c.2970-2972 del ATT) on

exon

17

Absence of Dermal neurofibromas

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No apparent

influence

of the NF1 gene

1132 Individuals from 313 families

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Cohort Family Studies

Trial

Patients

Families

MZ Twins

Siblings

Parent

-offspring

2

nd

degree3rd degreeTrial

PatientsFamilies

MZ TwinsSiblings

Parent

-offspring

2nd degree3rd degreeEaston et al 1993175486

76605443

Trial

Patients

Families

MZ Twins

Siblings

Parent

-offspring

2

nd

degree3rd degreeEaston et al 1993

17548

676

60

54

43

Szudek

et al 2000

904

373

ALL

Trial

Patients

Families

MZ Twins

Siblings

Parent

-offspring

2

nd

degree

3

rd

degree

Easton et al

1993

175

48

6

76

60

54

43

Szudek

et al 2000

904

373

ALL

Sabbagh

et al 2009

275

ALL

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NF1

75% of families have an interfamilial difference in clinical features

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NF1

+/-

p53

mpnst

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NF1

+/-

p53

+/-

NF1

+/-

p

53

+/-

p53

p53

NF1

NF1

p53

p53

NF1

NF1

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NF1 expression level

ch11

Nstr1

Nstr2

11q12-13

5p13-15

8q22-24

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Gene strategies to identify modifier genes

Approach scanning the whole genome

Approach focusing on candidate genes

Number of variants are generally small. However, detailed understanding of the candidate gene product.

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Candidate gene approachGenerate hypothesis and identifying candidate genes:

Understanding the biochemical function of NF1

Identifying variants (SNPs) near these genes

Genotyping these variants in a populations

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NF1

+/-

NF1

+/-

NF1

-

/-

NF1

+/-

Miss Match

Repair Gene

MLH1

MSH6

PMS2

MSH2

> Dermal

Neurofibroma

Plexiform

Neurofibroma

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NF1

+

/+

SKP NF1

+/-

NF1

+/+

NF1

+

/+

Males and Non-Pregnant Females

Pregnant Females

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NF1

+/-

NF1

+/-

NF1

-

/-

5% expressed estrogen receptors

75% expressed progesterone receptors

NF1 patients typically develop dermal neurofibromas around puberty

Increased potential for malignant transformation of plexiform neurofibromas with pregnancy

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Whole genomic gene approach

Pasmant

et al

CDKN2A-CDNK2B-ARF

ANRIL

Tag SNPs

In 1105 subjects (306 families):

Allele T of SNP rs2151280 was strongly associated with plexiform neurofibromas

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RefrencesNelson Textbook of pediatric, 19th

edition

Oxford Handbook of Clinical Medicine, 8

th

edition

Pasmant

E,

Vidaud

M,

Vidaud

D, Wolkenstein P. Neurofibromatosis type 1: from genotype to phenotype. J Med Genet 2012;49:483-489Heim RA, Silverman LM, Farber RA, Kam-Morgan LNW, Luce MC. Screening for truncated NF1 proteins. Nature Genet. 8: 218-219, 1994. Trovo-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clin. Genet. 70: 1-13, 2006. 

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Thank you