Wolf-Hirschhorn syndrome
Marcella Zollino
Genetica Medica U.C.S.C. Policlinico “A. Gemelli” Roma
WHS

Contiguous gene syndrome

Partial 4p deletion (4p16.3)

Clinical signs
“Greek warrior helmet profile”
MR
Pre- and postnatal growth retardation
Microcephaly
CHD
Midline defects
Renal abnormalities
Seizures
WHS: personal observations
84 patients
- familial (translocations) 10 (12%)
- de novo
74 (88%)
METHODS
• Conventional cytogenetics
• FISH with locus-specific probes (90) on 4p and all telomeres
• A-CGH (75 kb resolution Agilent 44K)
• Microsatellite segragation analysis
WHS: de novo rearrangements in 51 patients studied
with all telomeres, locus-specific FISH, or a-CGH
Type of the rearrangement
No
%
Isolated deletions
37
72
Unbalanced translocations
10
20
Dup/del 4p
3
6
der(4)(4qter→q32::4p15.3→qter)
1
2
t(4p;8p) (6)
t(4p;7p)
t(4p;11p)
t(4p;20q)
t(4p;Dp/Gp)
Dup/del
Duplication/deletion breakpoints
3.2 Mb
~10 Mb
Del 4p: 12 Mb
~10 Mb
-14
15.1 15.2 15.31 15.32 15.33
4p
16.1
16.2 16.3
WHS: de novo rearrangements
Unbalanced translocations
Dup/del
Der (4p;4q)
Isolated deletions
WHS: parental origin of de novo rearrangements
Maternal
10/44 (23%)
t(4p;8p)
5
t(4p;7p)
1
t(4p;20q)
1
del(4p) interstitial
1
del(4p) terminala
2
Paternal
Del(4p) terminal
34/44
(77%)
29
Del(4p) interstitial
2
t(4p;11p)
1
t(4p;acro p-arm)
1
der(4)(4qter→q32::4p15.3→qter)
1
a 1.5 Mb deletion, preserving the WHSCR-2, was detected in the mother of patient 12.
a
1
2
3
4
5
6
7
8
9
10
11
Cen
OR
7E162P
OR
7E43P
OR
OR
7E99P 4D12P
Proximal OR and distal OR on 4p16
OR
OR
OR
OR
7E86P 7E84P 7E85P 7E83P
OR
7E35P
-
-
-
-
-
-
-
-
-
1,8
1,9
33c6
2,25
S182
247f6
2,8
S180
21f12
3,3
S81
228a7
3,7
MSX-1
4,9
RP115,6-5,9
524D9
RP117-7,2
367J11
RP118,6-8,7
358C18
RP119
423D16
RP119.4
751L19
RP1113
731E20
RP1114.1
358H2
RP1114.6
81L15
RP1115.4
565F20
t(4p;3p) mat
-
145
t(4;13) (p16.;q33)
mat
-
-
50
t(4;13) (p16.1;p11)
mat
-
25
t(4;D/G)(p16.2;p11)
de novo
-
118
t(4;20)(p16.2; q13.3)
de novo
-
7
t(4;11) (p16.1;q23.3)
pat
-
116
t(4;11) (p16.1;q25)
mat
t(4;8) (p16.3;p23)
de novo
-
81
t(4;11)(p16.1;p15.5)
de novo
t(4 ;8)( p16.1;p23)
de novo
-
24
t(4;10) (p16.3;p15)
mat
87
t(4;7)(p16.3;p22.2)
mat
74
Patients
127
43
t(4;7) (p16.3;p23)
de novo
52
-
S43
MSX1
140
(familial or de novo):tot=18
t(4;8) (p16.3;p23)
de novo
pC678
S98
pC385.1
FGFR3
2
S3327
190b4
S96
48
t(4;8)(p16.1;p23) pat
CD2
40
t(4;8)(p16.1;p23)
de novo
S90
39
t(4;8)(p16.1;p23)
de novo
Tel
30
t(4;8)(p16.1;p23)
de novo
Probes
S3359
Distance from 4pter (Mb)
Locus
Unbalanced translocations
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
+
+
+
-
+
+
-
-
-
+
+
+
+
-
-
-
-
-
-
-
-
-
-
-
-
+
-
-
+
+
+
+
+
-
-
+
+
+
+
+
+
-
-
-
+
+
+
+
+
+
-
+
-
-
-
-
+
+
-
+
-
+
+
+
Patients No
Probes
pC847.351
CD2
pC678
pC385.12
190b4
19h1
108f12
33c6
161c2
79f5
212a9
185f6
247f6
21f12
228a7
MSX1
RP11-524D9
RP11-367J11
RP11-358C18
RP11-423D16
RP11-751L19
RP11-17I9
RP11-270I3
RP11-1J7
RP11-3M2
RP11-731E20
RP11-356H2
RP11-81L15
RP11-469O6
RP11-565F20
RP11-332D24
RP11-481K22
RP11-778B12
RP11-497E20
RP11-390C19
Distance
from
4pter
(Mb)
0,15
0,25
1,2
1,8
1,95
2
2,2
2,3
2,35
2,5
2,5
2,6
2,9
3,4
3,7
4,9
5,9
7,2
8,6
9
9,4
9,7
10,8
11,6
12,6
13
14,1
14,6
15
15,4
20
22
25,4
27
29,5
37
1
80
-
-
-
-
-
2
3
4
5
36
41
45
89
-
18
42
73
128
139
32
78
82
-
-
-
+
-
-
-
-
-
-
-
-
-
-
-
-
112
111
33
131
59
-
-
-
-
-
-
-
-
-
-
-
-
6
11
22
117
10
35
120
20
31
86
124
-
-
-
-
-
8
9
85
88
91
119
-
-
-
-
-
-
-
-
-
-
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
-
-
-
+
+
+
-
-
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
44
98
12
13
+
+
-
-
-
-
-
-
-
-
-
-
-
+
-
-
-
-
-
-
-
-
92
26
46
77
103
115
+
+
-
+
-
+
+
+
+
+
+
+
+
-
14
15
75
MG
97
-
+
+
+
+
+
+
+
0
Inversion
21
Paternally derived rearr
3
Inversion
6
Maternally derived rearr
5
Double anomalies
Inversion
Inversion
Isolated deletions
25
22
20
15
10
5
3
WHS: the basic genomic defect

Heterogeneous
- isolated deletions
- unbalanced de novo translocations
- dup/del 4p
- intrachromosome rearrangement

Great variability in individual 4p deletion size
1.9 - 29 Mb

Rearrangements not mediated by ORs

Usually paternal in origin
4p deletion (Mb)
Typical face
Growth delay
Seizures
MR
Microcephaly
Cleft palate
Hypospadias
CHD
Renal anomalies
1.9-2.2
2.2-3.4
3.4
WHS
Clinical categories
WHS: “classical” phenotype
Large 4p deletion
 Characteristic face
 Severe MR
 Severe growth delay
 Seizures
 Microcephaly
 CHD
 Midline defects
 Renal anomalies
WHS: “mild” phenotype
Small deletion (< 3 Mb)





Characteristic face
Mild MR
Growth delay
Seizures
Cleft palate
No other malformations
OFC possibly normal
WHS: 4p deletion > 20 Mb
Severe MR
Absent communication
No independent walking
Severe scoliosis
Psychiatric problems
Major malformations
WHS: clinical categories
• Classical
• Mild
• Severe: WHS ?
WHS: prognostic factors
 Extent of the 4p deletion
“cut-off” 3 Mb
 Double chromosome imbalance
 Seizures: independent prognostic factor
WHS: pathogenesis
 What to call WHS
 What to consider the WHS critical region
 Can be WHS a single-gene disorder?
 Pathogenic genes?
WHS: the core phenotype
 Typical face
 Mental retardation
 Growth delay
 Seizures (or EEG anomalies)
WHSCR (Wright et al 1997)
4p16.3
Rauch, 2001
WHSC2 WHSC1
cen
LETM1
1.9 Mb
S166
S3327
58b6 158b1 96a2
174g8
27h9
WHSCR
1.8 Mb
1.5 Mb
//
tel
S98 FGFR3 S168 S96
190b4 75b9
19h1 184d6 184O23
pC385.12
pC678
WHSCR-2 (Zollino et al 2003)
4p16.3
Rauch, 2001
patient MG + Rodriguez’s patient (tot 2)
WHSC2 WHSC1
cen
LETM1
1.9 Mb
S166
174g8
27h9
WHSCR
1.5 Mb
//
S3327
58b6 158b1 96a2
1.8 Mb
tel
S98 FGFR3 S168 S96
190b4 75b9
pC385.12
19h1 184d6 184O23
WHSCR-2
pC678
WHSCR-2
4p16.3
t(4p;12p)
Rauch, 2001
Mother of case 012
patient MG + Rodriguez’s patient (tot 2)
WHSC2 WHSC1
cen
LETM1
1.9 Mb
S166
174g8
27h9
WHSCR
1.5 Mb
//
S3327
58b6 158b1 96a2
1.8 Mb
tel
S98 FGFR3 S168 S96
190b4 75b9
pC385.12
19h1 184d6 184O23
WHSCR-2
pC678
The mother
+-
WHS 012
Tel
1,5 Mb
F26
3,2 Mb
pC847.351 O,15Mb
+-
IS28
+-
+-
S96
WHSCR2
+-
++
1,2 Mb
FGFR3
pC385.12 1,8Mb
S3327
190b4
1,95Mb
S43
33c6
2,3Mb
S182
247f6
2,9Mb
S180
++
pC678
21f12
+ -
+-
3,4Mb
++
Del 4p 1.5 Mb
WHSCR-2, WHSCR, LETM1, WHSC1 preserved
15 mo
BW: 3500 gr
Walking: 15 months
Language: 14 months
3 ys
Seizures with fever
(6 episodes 1-5 ys)
Normal growth
MR borderline
56 ys
Facies: ?
No growth delay
MR borderline
South, 2007 ring 4
Concolino,2007 ring 4
4p16.3
t(4p;12p)
Rauch, 2001
Mother of case 012
patient MG + Rodriguez’s patient (tot 2)
WHSC2 WHSC1
cen
LETM1
1.9 Mb
S166
174g8
27h9
WHSCR
1.5 Mb
//
S3327
58b6 158b1 96a2
1.8 Mb
tel
S98 FGFR3 S168 S96
190b4 75b9
pC385.12
19h1 184d6 184O23
WHSCR-2
pC678
WHS
Phenotypic map
WHS: clinical signs
%
4p del
Typical face
100
1.9-29 Mb
MR
100
1.9-29 Mb
Growth delay
100
1.9-29 Mb
Seizures (or EEG +)
100
1.9-29 Mb
95
> 2.5 Mb
Microcephaly
Head circomference normal in 1.9 Mb and 2.2 Mb (2)
deletion
WHS: Midline Defects
%
4 p del
Cleft palate
27
> 2.5 Mb
Hypospadias
19
> 3.5 Mb
Cleft lip and palate
2
20 Mb
WHS: major malformations
%
CHD
del4p
50
> 5 Mb
34
> 8 Mb
pulmonic stenosis
ASD/VSD
Renal anomalies
renal hypoplasia
Colobomas
iris
8.6
> 12 Mb
3,4 Mb
21f12
4,7 Mb
MSX1
Renal anomalies
CHD
Hypospadias
Cleft palate
Microcephaly
Growth delay
1.9
2.5
2.3
0.4 Mb
247f6
1.9
1.5
0.4 Mb
2,9 Mb
108f12
1.9
0.7 Mb
WHSCR
WHSCR-2
2,2 Mb
1.2
1.4 Mb
0.7 Mb
1 Mb S96
0
Facies
0.5 0.5
0,15 Mb F26
1.7 Mb S113
1,8 Mb FGFR3
LETM1
WHSC1
1,9 Mb S3327
MR
Seizures
Tel
2.7
3.5
5
4 Mb
9 Mb
9
Cen
8
Seizures
Facies
Tel
0,5Mb
0,15 Mb F26
1,2Mb
247f6
3,4 Mb
21f12
4,7 Mb
MSX1
9 Mb
Cen
1,9Mb
1,5Mb
0.4 Mb
108f12
1,9Mb
0.7 Mb
2,9 Mb
WHSCR
2,2 Mb
WHSCR-2
1.7 Mb S113
1,8 Mb FGFR3
1,5Mb
1 Mb S96
1,9 Mb S3327
Growth
delay
1,9Mb
Distanza dal
tel. (Mb)
-PDE6B
0,60
-ATP51
0,65
-MYL5
0,66
-RNF3
0,75
-CPLX1
0,78
-GAK
0,85
-SLC26A1 0,96
-IDUA
0,97
-FGFRL1 1
-TBP1
1,1
-MAEA
1,2
-SLBP
1,6
-TACC3
1,7
-FGFR3
1,78
-LETM1
1,86
-WHSC1 1,9
WHS: gene mutations?
WHSC1: atypical WHS
 Growth delay
 MR
 Facial characteristics
No seizures
WHS: the multigenic
pathogenesis
 Facial characteristics: terminal 1.9 Mb
WHSC1 (1.9 Mb) + more distal genes
 Seizures: terminal 1.8 Mb
LETM1 (1.8 Mb) + more distal genes
 Growth delay: 500 kb (1.9-1.4 Mb from the telomere)
no candidate genes (WHSC1?)
WHS: gene theraphy ?

Pathogenic mechanism: haploinsufficiency

Unaltered copy of each gene on the homologous

Healthy alleles ideal candidates for drug theraphy
Strategies
1)
Small molecules stimulating transcription
2)
Up-regulation of protein activity