Файл: Genetics [BRS].pdf

d.

40% of Type I OI affected individuals (i.e., milder forms of OI) inherit a mutant
gene from an affected parent whereas 

60% have a de novo mutation.  100% of 

type II and III OI affected individuals (i.e., more severe forms of OI) have a de novo
mutation.

e. Prevalence.

The prevalence of all types of OI is 1/15,000 births in a Finnish population.

f. Clinical features include:

extreme bone fragility with spontaneous fractures, short

stature with bone deformities, grey or brown teeth, 

blue sclera of the eye

, and progres-

sive postpubertal hearing loss. Milder forms of OI may be confused with child abuse.
Severe forms of OI are fatal in utero or during the early neonatal period. 

2. Classic-type Ehlers Danlos syndrome (EDS). 

a.

EDS is an autosomal dominant genetic disorder caused by mutations where at least
two different genes have been implicated thus far:

i. COL5A1 gene

on 

chromosome 9q34.2-q34.3

for 

collagen pro

-1 (V) chain of Type V pro-

collagen 

ii. COL5A2 gene

on 

chromosome 2q31

for 

collagen pro

-2 (V) chain of Type V procollagen 

b.

EDS is most commonly caused by a 

nonsense mutation, frameshift mutation

, or a 

RNA

splicing mutation

(that forms a premature STOP codon, shifts a reading frame, or pro-

duces unstable mRNAs). 

c.

50% of EDS affected individuals inherit a mutant gene from an affected parent
whereas 

50% have a de novo mutation. 

d. Prevalence.

The prevalence of EDS is 1/20,000 births.

e. Clinical features include: extremely stretchable and fragile skin, hypermobile joints,

aneurysms of blood vessels, rupture of the bowel, abnormal wound healing, and
widened atrophic scars. 

3. Marfan syndrome (MFS). 

a.

MFS is an autosomal dominant genetic disorder caused by a mutation in the 

FBN1 gene

on 

chromosome 15q21.1

for the 

f ibrillin-1

protein, which is an essential component of

microfibrils

found in both elastic and nonelastic tissue. Microfibrils play a role in the

formation of the elastic matrix (i.e., 

elastic fibers

), elastic matrix-cell attachments, and

the regulation of growth factors. 

b.

MFS is caused by 

200 different mutations and no common mutation is associated

with any population.

c.

75% of MFS affected individuals inherit a mutant gene from an affected parent
whereas 

25% have a de novo mutation. 

d. Prevalence. 

The prevalence of MFS is 1/5,000 to 10,000 births. 

e. Clinical features include:

unusually tall individuals, exceptionally long, thin limbs, pec-

tus excavatum (“hollow chest”), scoliosis, 

ectopia lentis (dislocation of the lens),

severe

near-sightedness (myopia), 

dilatation or dissection of the aorta

at the level of the sinuses

of Valsalva which may lead to cardiomyopathy or even a rupture of the aorta, dural
ectasia, and mitral valve prolapse.

160

Board Review Series Genetics

VIII. NEURAL CREST CELL MIGRATION

The neural crest cells differentiate from cells located along the lateral border of the neural
plate, which is mediated by 

BMP-4

and 

BMP-7 (body morphogenetic protein).

The differentia-

tion of neural crest cells is marked by the expression of 

slug

(a zinc-finger transcription fac-

tor) which characterizes cells that break away from the neuroepithelium of the neural plate
and migrate into the extracellular matrix as mesenchymal cells. Neural crest cells undergo a
prolific migration throughout the embryo (both the cranial region and trunk region) and
ultimately differentiate into a wide array of adult cells and structures. 

Neurocristopathy

is a

termed used to describe any disease related to maldevelopment of neural crest cells.

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A. Waardenburg syndrome Type 1 (WS Type 1). 

1.

WS type 1 is an autosomal dominant genetic disorder caused by mutation in the 

PAX3

gene

on 

chromosome 2q35

for the 

paired box protein PAX3 .

The PAX genes are characterized

by a 128 amino acid DNA-binding domain called a paired box.

2.

Paired box protein PAX3 is one of a family of nine human PAX genes coding for 

DNA-binding

transcription factors

that are expressed in the early embryo and regulate neural crest-

derived cell types, including melanocytes. . 

3.

The mutations of the PAX3 gene include 

missense, nonsense, frameshift, whole gene dele-

tions, intragenic deletions,

and 

RNA splicing mutations

; all of which result in a 

loss-of-function

mutation

.

4.

90% of WS affected individuals inherit a mutant gene from an affected parent whereas

10% have a de novo mutation. The de novo mutations usually occur during spermatoge-
nesis in the unaffected advanced-aged father. Chances of WS type 1 increase with increas-
ing paternal age.

5. Prevalence.

The prevalence of WS type 1 is 1/20,000 to 40,000 births. WS type 1 is respon-

sible for 

3% of congenitally deaf children. 

6. Clinical features include:

dystopia canthorum (lateral displacement of the inner 

canthi), growing together of eyebrows, lateral displacement of lacrimal puncta, a 
broad nasal root, heterochromia of the iris, congenital deafness or hearing impair-
ment, and piebaldism including a white forelock and a triangular area of hypopigmen-
tation.

B. Nonsyndromic Congenital Intestinal Aganglionosis (Hirschsprung disease; HSCR). 

1.

Nonsyndromic HSCR is an autosomal dominant genetic disorder associated with muta-
tions where at least six different genes have been implicated thus far: 

a. RET (rearranged during transfection) gene

on 

chromosome 10q11.2

for a 

receptor tyrosine

kinase 

(

90% of HSCR cases)

b. GDNF gene

on 

chromosome 5p13.1-p14

for 

glial cell line-derived neurotrophic factor

c. NRTN gene

on 

chromosome 19p13.3

for 

neurturin

d. EDNRB gene

on 

chromosome 13q22

for the 

endothelin B receptor

e. EDN3 gene

on 

chromosome 20q13.2-q13.3

for 

endothelin-3

f. ECE1

on 

chromosome 1p36.1

for 

endothelin-converting enzyme 

2.

RET protein is expressed by enteric neuronal precursor cells after they leave the neural
tube and throughout their colonization of the gut tube. RET ligands are 

GDNF 

and 

NRTN

which are expressed by nearby mesenchymal cells. 

3.

The mutations in the RET gene result in a 

loss-of-function mutation

. 

4.

A significant proportion of HSCR affected individuals inherit a mutant gene from a
completely unaffected parent (because of incomplete penetrance or variable expres-
sivity the parent is unaffected resulting in what appears to be a negative family his-
tory). A small proportion of HSCR affected individuals inherit two different 
mutant genes with each parent contributing a single mutant allele (i.e., digenic inher-
itance). The proportion of HSCR affected individuals with a de novo mutation is
unknown. 

5. Prevalence.

The prevalence of HSCR is 1/5000 births. 80% of HSCR affected individuals

have aganglionosis restricted to the rectosigmoid colon (“short segment disease”). Fifteen
percent to 20% of HSCR affected individuals have aganglionosis that extends proximal to
the sigmoid colon (“long segment disease”). Two percent to 10% of HSCR affected indi-
viduals have trisomy 21 (Down syndrome). This association between trisomy 21 and
HSCR remains unexplained. 

6. Clinical findings include:

arrest of the caudal migration of neural crest cells resulting in

the absence of ganglionic cells in the myenteric and submucosal plexuses; abdominal
pain and distension; 

inability to pass meconium within the first 48 hours of life;

gushing of

fecal material upon a rectal digital exam; constipation; emesis; a loss of peristalsis in
the colon segment distal to the normal innervated colon; and the failure of 
internal anal sphincter to relax following rectal distention (i.e., abnormal rectoanal
reflex).

Chapter 15

Genetics of Development

161

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C. Orofacial clefting. 

1.

Orofacial clefting is a multifactorial genetic disorder associated with mutations where at
least five different genes have been implicated thus far: 

a. DLX 1-6 (distal  less homeobox) gene family

on 

chromosome 2q32, 2cen-q33,17q21.3-

q22,17q21.33,7q22

, and 

7q22

, respectively, for various 

homeodomain gene regulatory proteins

b. SHH (sonic hedgehog) gene

on 

chromosome 7q36

for the 

shh protein

c. TGF-

 (transforming growth factor) gene

on 

chromosome 2p13

for the 

TGF-

 variant protein

d. TGF-

 gene

on 

chromosome 14q24

for the 

TGF-

 protein

e. IRF-6 (interferon regulatory factor) gene

on 

chromosome 1q32.3-q41

for the 

IRF6 transcrip-

tion factor

.

2.

Orofacial clefting has a 

multifactorial inheritance

(i.e., a genetic component interacting

with the environment). Orofacial clefting is a genetically complex event; a single gene
mutation causing orofacial clefting probably does not occur. 

3.

Environmental factors that may play a role in orofacial clefting involve exposure of the
fetus to 

phenytoin, sodium valproate

, 

methotrexate, 

and

folate deficiency

. 

4.

The most common craniofacial birth defect is the orofacial cleft, which consists of 

cleft lip with

or without cleft palate (CL/P)

or 

isolated cleft palate (CP).

CL/P and CP are distinct birth defects

based on their embryological formation, etiology, candidate genes, and recurrence risk. 

5. Prevalence.

CL/P is more common than CP and varies by ethnicity. The prevalence of

CL/P is 1/500 births in American Indian and Asian populations, 1/1,000 births in
Caucasian populations, and 1/2,000 in the African American population. CL/P occurs
more frequently in males. The prevalence of CP is 1/2,500 births occurs in 2,500 births,
does not show ethnic variation, and occurs more frequently in females. 

6. Clinical features include:

Cleft lip (unilateral cleft lip on the left side is most commonly

seen); cleft palate; a combination of both cleft lip and cleft palate; and other associated
abnormalities in the central nervous system; skeletal system; cardiovascular system; and
all tissue of neuroectodermal origin. 

D. Treacher Collins Syndrome (or Mandibulofacial Dysostosis; TCS).

TCS belongs to a category of

first arch syndromes, 

which result from a lack of neural crest cell migration into pharyngeal

arch 1, and produces various facial anomalies. There are two well-described first arch syn-
dromes: TCS and 

Pierre Robin syndrome

. 

1.

TCS is an autosomal dominant genetic disorder caused by a mutation in the 

TCOFI gene

on

chromosome 5q32-q33.1

for the 

treacle protein. 

2.

The treacle protein is a nucleolar protein related to the nucleolar phosphoprotein 

Nopp140

both of which contain 

LIS1 motifs

leading to the speculation of 

microtubule dynamics

involvement. In addition, treacle interacts with the small nucleolar ribonucleoprotein

hNop56p

leading to the speculation of 

ribosomal biogenesis

involvement. 

3.

100 mutations in the TCOF1 gene have been identified with 

frameshift mutations

forming

a premature STOP codon, which is the most common type of mutation. The mutations in
the TCOFI gene result in a 

loss-of-function mutation

.

4.

40% of TCS affected individuals inherit a mutant gene from an affected parent whereas

60% have a de novo mutation.

5. Prevalence.

The prevalence of TCS is 1/10,000-50,000 births. 

6. Clinical features include:

hypoplasia of the zygomatic bones and mandible resulting in mid-

face hypoplasia, micrognathia, and retrognathia; external ear abnormalities including small,
absent, malformed, or rotated ears; and lower eyelid abnormalities including coloboma.

162

Board Review Series Genetics

IX. SUMMARY TABLE OF DEVELOPMENTAL DISORDERS (Table 15-2)

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Chapter 15

Genetics of Development

163

t a b l e

15-2

Developmental Disorders

Genetic Disorder

Gene/Gene Product Chromosome

Clinical Features

Determination of left/right axis
Primary ciliary dyskinesia

Growth and differentiation 
Achondroplasia

Hypochondroplasia 

Thanatophoric dysplasia

Crouzon syndrome

Chronic cough; chronic rhinitis; chronic

sinusitis; chronic/recurrent ear infections;
recurrent sinus/pulmonary infections due
to a defect of cilia in the respiratory path-
ways; neonatal respiratory distress; digi-
tal clubbing; sterility in males (retarded
sperm movement); situs inversus totalis
(mirror-image reversal of all visceral
organs with no apparent consequences;
PCD with situs inversus totalis is called
Kartagener syndrome

); heterotaxy (dis-

cordance of right and left patterns of ordi-
narily asymmetrical structures with signif-
icant malformations; for example asplenia
or polysplenia); the gold standard diag-
nostic test is the appearance of ciliary
ultrastructural defects obtained by elec-
tron microscopy of a respiratory epithe-
lium biopsy.

Short stature, proximal shortening of arms

and legs with redundant skin folds, limita-
tion of elbow extension, trident configura-
tion of hands, bow legs, thoracolumbar
gibbus in infancy, exaggerated lumbar
lordosis, large head with frontal bossing,
and midface hypoplasia, mental function
is not affected.

Short stature, stocky build, disproportion-

ately short arms and legs, broad, short
hands and feet, mild joint laxity, and
macrocephaly. The skeletal features 
are very similar to AC but generally 
are more mild with less craniofacial
involvement.

Short ribs, narrow thorax, macrocephaly,

distinctive facial features, brachydactyly,
hypotonia, and redundant skin folds along
the limbs; children with TD usually die in
the perinatal period with only a few sur-
vivors into early childhood; a narrow tho-
racic cage which leads to respiratory
compromise; curved long bones; type 1
TD is characterized by micromelia with
bowed femurs and generally without a
cloverleaf-shaped skull; type 2 TD is char-
acterized by micromelia with straight long
bones and generally with a cloverleaf-
shaped skull.

Premature craniosynostosis, midface

hypoplasia with shallow orbits, ocular
proptosis, mandibular prognathism, nor-
mal extremities, progressive hydro-
cephalus, and no mental retardation.

DNAH5 gene/ciliary dynein axonemal

heavy chain 5 
5p15-p14

DNAI1 gene/dynein axonemal inter-

mediate chain 1 
9p21-p13

FGFR3 gene/fibroblast growth factor

receptor 3
4p16.3

FGRR3 gene/fibroblast growth

factor receptor 3
4p16.3

FGFR3 gene/fibroblast growth 

factor receptor 3
4p16.3

FGFR2 gene/fibroblast growth 

factor receptor 2
10q25-q26

(continued)

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164

Board Review Series Genetics

t a b l e

15-2

(continued)

Genetic Disorder

Gene/Gene Product Chromosome

Clinical Features

Extreme bone fragility with spontaneous

fractures, short stature with bone defor-
mities, grey or brown teeth, blue sclera of
the eye, and progressive postpubertal
hearing loss. Milder forms of OI may be
confused with child abuse. Severe forms
of OI are fatal in utero or during the early
neonatal period. 

Extremely stretchable and fragile skin, hyper-

mobile joints, aneurysms of blood vessels,
rupture of the bowel, abnormal wound
healing, and widened atrophic scars.

Unusually tall individuals; exceptionally long,

thin limbs; pectus excavatum (“hollow
chest”); scoliosis; ectopia lentis (disloca-
tion of the lens); severe near-sightedness
(myopia); dilatation or dissection of the
aorta at the level of the sinuses of
Valsalva, which may lead to cardiomy-
opathy or even a rupture of the aorta,
dural ectasia, and mitral valve prolapse.

Dystopia canthorum (lateral displacement of

the inner canthi); growing together of
eyebrows; lateral displacement of
lacrimal puncta; a broad nasal root; hete-
rochromia of the iris; congenital deafness
or hearing impairment; and piebaldism,
including a white forelock and a triangu-
lar area of hypopigmentation.

Arrest of the caudal migration of neural crest

cells resulting in the absence of ganglionic
cells in the myenteric and submucosal
plexuses; abdominal pain and distension;
inability to pass meconium within the first
48 hours of life; gushing of fecal material
upon a rectal digital exam; constipation;
emesis; a loss of peristalsis in the colon
segment distal to the normal innervated
colon; and the failure of internal anal
sphincter to relax following rectal disten-
sion (i.e., abnormal rectoanal reflex).

Cleft lip (unilateral cleft lip on the left side is

most commonly seen); cleft palate; a
combination of both cleft lip and cleft
palate; and other associated abnormali-
ties in the central nervous system, skele-
tal system, cardiovascular system, and all
tissue of neuroectodermal origin.

Hypoplasia of the zygomatic bones and

mandible resulting in midface hypoplasia,
micrognathia, and retrognathia; external
ear abnormalities including small, absent,
malformed, or rotated ears; and lower
eyelid abnormalities including coloboma.

COL1A1 gene/collagen pro

-1(I)

chain of Type I procollagen
17q21.3-q22

COL1A2 gene/collagen pro

-2 (I)

chain of Type I procollagen
7q22.1

COL5A1 gene/collagen pro

-1 (V)

chain of Type 5 procollagen
9q34.2-q34.3

COL5A2 gene/collagen pro

-2(V) 

chain of Type V procollagen
2q31

FBN1 gene/fibrillin-1

15q21.1

PAX3 gene/paired box protein PAX3

2q35

RET gene/receptor tyrosine kinase

10q11.2

GDNF gene/glial cell-line derived 

neurotrophic factor
5p13.1-p14

NRTN gene/neurturin

19p13.3

EDNRB gene/endothelin B receptor

13q22

EDN3 gene/endothelin 3

20q13.2-q13.3

DLX 1-6 gene family/homeodomain

gene regulatory proteins
2q32, 2cen-q33,17q21.3-q22,
17q21.33,7q22, 7q22

SHH gene/shh protein

7q36

TGF-

 gene/TGF-variant protein

2p13

TGF-

 gene/TGF-protein

14q24

IRF-6 gene/IRF6 transcription factor

1q32.3-q41

TCOFI gene/treacle protein

5q32-q33.1

Formation of the extracellular matrix
Osteogenesis imperfecta 

Classic-type Ehlers 
Danlos syndrome

Marfan syndrome

Neural crest cell migration
Waardenburg syndrome

Congenital intestinal 

aganglionosis

Orofacial clefting

Treacher Collins 

syndrome

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