tl_files/tiny_templates/Bilder TL/Header-sSMC.jpg

- sSMC -

CHROMOSOME 4

References

 

             
  Cases without
clinical findings
5 Cases with
clinical findings
19 symptoms  
  similar imbalances - no clinical findings similar imbalances with clinical findings  
  Cases with
unclear clinical correlation
Cases with
neocentromeres
1 tumor
0
 
  similar imbalances  
      DISCLAIMER      

In general 70% of sSMC carriers are clinically normal. The figures here
are based on the bias, that mainly clinically aberrant cases are reported in literature!

           
  UPD (uniparental disomy) cases: UPD 4
mat
UPD 4
pat
UPD 4
unclear
 
           

 


the probably non-dosage sensitive pericentric region of chromosome 4


SCHEMATIC CYTOGENETIC DEPICTION

tl_files/tiny_templates/Bilder TL/sSMC/sSMC-4.jpg



SCHEMATIC MOLECULARGENETIC DEPICTION

acc. to UCSC Genome Browser on Human Mar. 2006 assembly [UCSC hg18, 2006]
and available BAC-data/ array-data from cases marked *** mentioned below [MB]

 

critical region 39.80 --- 44.03 uncritical region [48.70 centromere 52.40] uncritical region 63.5 --- ? critical region

Below adapted for UCSC hg19, 2009

critical region 40,10 --- 44.13 uncritical region [48.20 centromere 52.70] uncritical region 63.70 --- ? critical region

 


Clinical symptoms of centromere-near proximal imbalances

 

chromosomal region

4p - proximal 4q - proximal
symptoms
developmental delay (100 %) 60 %
dysmorphic face 0 % 40 %
finger or toe/foot malformations 0 % 20 %
hypertonia 0 % 20 %
mental retardation 0 % 40 %
macrocephaly 0 % 20 %
overgrowth 0 % 40 %
number of cases (marked with “°” below) 1 5
 

References

Cases without clinical findings (O)

 

 
  case no. gender/
age at diagnosis
studied
material
de novo/
inherited
GTG-banding result
grade of mosaicism
final result of the sSMC test
methods
clinical symptoms reference  
  04-O-
p13/
1-1
moved to 04-W-p14/1-2  
  ***
04-O-
p13/
2-1

***
male/
prenatal
AF, PBL de novo 47,XY,+mar[14]/
46,XY[6]
interphase of PBL at delivery: 189/200 with sSMC
mar(4)(:p13q13.1:)
array: 44.03-62.63 MB
array-CGH; cep 4 advanced maternal age and abnormal serum screening; normal at birth and at age of 1y {36} case 2  
  ***
04-O-
p12/
1-1
***
male/
adult
PBL de novo 47,XY,+mar[23]/
46,XY[27]
r(4)(::p12q13.1::)
~2.5 MB in 4p and ~8.5 Mb in 4q euchromatin
pericentic BAC set infertility and asthenoteratozoospermia {43} case 3
{45} case 4-1
 
  04-O-
p12/
2-1
male/
30y
PBL
bucchal cells
n.a. PBL: 47,XY,+mar[100%]
BC: sSMC in 45-55%

r(4)(::p12q13.1::)
46,866,413-63,393,712 [hg19]

array-CGH case possibly identical to 04-CO-1; normal male; finding incidentially

{0} provided by Dr. E.M. Vestergaard, Aarhus, Denmark

 
  04-O-
p11/
1-1
male/
47y
PBL n.a. 47,XY,+mar[62%]/
46,XY[38%]

min(4)(:p11q12:)

cenM, subcenM normal male, infertile {45} case 4-2
 
  04-O-
p11/
2-1
female/
prenatal
CVS/ AF de novo 48,XX,+marx2[1]/
47,XX,+mar[17]/
46,XX[8]
trisomy 4 mosiac in placenta
min(4)(:p11q11:) cenM, subcenM IUGR due to small palcenta; (small) normal child born and normal at 1of age {0} provided by Dr. Daumer-Haas; Munich, Germany  
  ***
04-O-
p11/
3-1
***

female/
43y
PBL n.a. 47,XX,+mar[35]/
46,XX[15]

r(4)(::p11q13.1::)
FISH: breaks betw. RP11-100N21 and centromere = between 47,71 and 48,20 Mb;
and betw. RP11-257A22 and RP11-204H9 = 63,770,878 and 65,296,627  (GRCH37/hg19)

cenM, subcenM; 1Mb-probeset
mentally normal female, studied after abortion, (also present: overgrowth; macrocephaly; diabetes)
{0} provided by Drs Wagner and Stibbe, Hannover, Germany.  
                     

 

O-Cases with similar imbalances NOT caused by sSMC (O-IMB)

none reported yet


O-cases with unclear/insufficient characterization of the sSMC (CO):

 

 
  case no. gender/
age at diagnosis
studied
material
de novo/
inherited
GTG-banding result
grade of mosaicism
final result of the sSMC test
methods
clinical symptoms reference  
  04-
CO-1
male/
1m
PBL de novo 47,XY,+mar[70%]/
46,XY[30%]
mar(4) all available centromeric probes normal at age of 7y {8} case 39997  
                     

 


References

Cases with clinical findings (W)

 

 
  case no. gender/
age at diagnosis
studied
material
de novo/
inherited
GTG-banding result
grade of mosaicism
final result of the sSMC test
methods
clinical symptoms reference  
  04-W-
p15.3/
1-1
see McCl-04-W-p15.3/1-1
{17}  
  04-W-
p15.3/
2-1
n.a./
prenatal
AF de novo 47,+mar min(4)(pterq10:) n.a. ultrasound abnormalities, TOP {33} 1 case  
  04-W-
p1?5/
1-1
male/
2.5 y
PBL n.a. 47,XY,+r[4]/
46,XY[26]
min(4)(:p1?5q12:) cenM; subcenM DD, dwarphism {0} provided by Dr. Junge, Dresden, Germany  
  04-W-
p14/
1-1
see 04-U-8    
  ***
04-W-
p14/
1-2 °
***
female/
prenatal
AF; Placenta de novo 47,XX,+mar[29]/
46,XX[12]
in placenta mar in 60% of cells
min(4)(:p14q11.1:)
array
-data: 39.8-48.9MB
M-FISH; subcenM; array-CGH; UPD-test see below {34}  
Amniocentesis due to nuchal translucency 3.9mm in week 14+3 , nose bone 1.5mm in week 13;  born in week 39 of pregnancy, weight 3740g. At age of 3 years 6 months the patient has no external malformations; size, weight and head circumference are all at 50th percentile. She showed psychomotor retardation, i.e. sitting with 8 months, walking with 1 year of age, delayed language development, now speaking 4-5 word sentences.
  04-W-
p12/
1-1
see McCl-04-W-p12/1-1
{22}
{26} case 7
 
  04-W-
p12/
2-1
male/
19m
PBL maternal
(in mother in 67% of PBL)
47,XY,+r[21]/
46,XY[9]
r(4)(::p?12q?12::)* cep probes, wcp 4 see below {31}  
In child: at 1 y bilateral cataracts, failure to thrive, hyperactivity;
In mother and child: relative microcephaly, triangular shape of face, down slanted and prominent eyes, broad tip of the nose, broad palms and soles, hyperpigmented areas of skin, wide sandal gaps.
04-W-
p12/
2-2
male/
4y
PBL de novo 47,XY,+mar[8]/
46,XY[42]
min(4)(:p12q12:) cenM; subcenM see below {0} provided by Marija Vesic, Belgrade, Serbia
walking at 19 months, no speech, mental retardation, sleep disturbance, self injury, macrocrania, large prominent ears, short nose, short hands and fingers
  04-W-
p12/
3-1
n.a./
postnatal
PBL paternal 47,+mar[60%]/
46[40%]
r(4)(::p12q13.2::)*
size in p 4.2 MB and in q 18.0MB
subcenM with 3 BACs; array-CGH see below {26} case 8  
DD; walked at 18 months of age; attention deficit hyperactivity disorder (ADHD); unilateral partial vision loss (etiology unknown); mild to moderate dysmorphic features; Tourette syndrome; Father has marker in 19 of 32 (= 60%) of peripheral lymphocytes. Father has mild intellectual disabled
  04-W-
p12/
3-2
female/
prenatal
AF,
other tissues
de novo 47,XX,+mar[17]/
46,XX[19]
in other tissues diff. mosaics observed
r(4)(::p12q13.2::)
arrayCGH: 46.18-67.85 MB
SKY; array CGH see below {26} case 9  
Amniocentesis due to advanced maternal age; TOP; autopsy revealed hypertelorism, epicanthic folds, a prominent nose, a triangular face, low-set ears, clinodactyly of the fingers, and small big toes.
  04-W-
p11/
1-1
female/
1y
PBL n.a. 47,XX,+mar[26]/
46,XX[4]
min(4)(:p11q11:) cenM, subcenM;
UPD-test
see below {0} provided by Dr. A. Dufke, Tübingen, Germany  
As newborn hypotrophy; born in week 38+6, weight 2250g, length 47cm, OFC 31cm; at 13m psychomotor retardation (no sitting up) microcephaly (P3), dystrophy weight 7.35 k, length 70cm (P3), slightly dysmorphic (form of the head, large sutura metopica and ears, short neck, deep voice).
  04-W-
p11/
1-2  °
male/
3y
PBL n.a. 47,XY,+mar[100%] min(4)(:p11q12:)
array: 52.43-57.74
cenM, subcenM;
aCGH
developmental delay {0} provided by Jason Anderson, Brisbane, Australia  
  04-W-
p11/
2-1  °
 
male/
prenatal
AF and PBL
(EKF-
cellbank)
de novo 47,XY,+mar[24]/
46,XY[16]
in PBL: 47:13
min(4)(:p11q12:)[9]/ min(4)(:q12p11:
:p11
q12:)[1]
cenM, subcenM see below {0} provided by Dr. C. Sarri, Athens, Greece  
mild motor retardation compared to twin brother; no morphogenetic variants other than mild blepharophimosis inherited from mother; mild hypertonia and irritability; two central incisors in the mandible. Brain and kidney, U/S, hearing evoked potentials, and ophthalmological investigation gave normal results.
  04-W-
p11/
2-2   °

female/
prenatal
AF n.a. 47,XX,+mar[100%] mar(4)(:p11q12:)
array: 52.38-54.86
aCGH see below {40} case 5
 
 
TOP; Dysmorphic features: hypertelorism, long philtrum
  04-W-
p10/
1-1 °
male/
27y
PBL de novo 47,XY,+r[100%] r(4)(::p10q12::) all centromeric probes; wcp 4 see below {13} case B  
Pregnancy and birth normal; motor development delayed from birth on; in late teens diagnosed with insulin-dependent diabetes mellitus; at 27y severe mental retardation, no development of language skills; height 160cm, weight 76 cm, HC 98th percentile, central obesity with gynecomastia and kyphosis, dysmorphic face (narrow forehead, ridged occiput, downwards slanting palpebral fissures, down-turned mouth, short philtrum, narrow pinna), narrow fingers with bilateral clinodactyly of 5th finger, syndactyly of toes 2 and 3
  04-W-
p10/
1-2 °
female/
6y
PBL de novo 47,XX,+mar/
48,XX,+mar,+mar/
49,XX,+mar,+mar,+mar [82%]/
46,XX[18%]
min(4)(:p10q13:)
(sSMC is derivative of a maternal chromosome 4)
CGH, cep 4, centromere near probes;
UPD-test
developmental delay, minor facial dysmorphism, postnatal overgrowth {20; 23}  
                     

 

W-Cases with similar imbalances NOT caused by sSMC (W-IMB):

 

 
  case no. gender/
age at diagnosis
studied
material
de novo/
inherited
GTG-banding result and FISH result incl. grade of mosaicism test
methods
clinical symptoms reference  
  04-W-
IMB-
q12/
1-1
male/ 2.7y PBL de novo 46,XY,dup(4)(q12q13) n.a. microcephaly, mental retardation, and minor facial anomalies {28}  
  04-W-
IMB-
q12/
2-1
female/
6y
PBL maternal
(balanced)
46,XX,der(18)ins(18;4)(q22;q12q13) n.a. At 6y short stature, microcephaly with brachycephaly, bilateral epicantal fold, microdontia, pronounced philtrum, and other minor dysmorphic signs {29}  
                   


W-cases with unclear/insufficient characterization of the sSMC (CW):

 

 
  case no. gender/
age at diagnosis
studied
material
de novo/
inherited
GTG-banding result
grade of mosaicism
final result of the sSMC test
methods
clinical symptoms reference  
  04-
CW-1
male/
prenatal
AF de novo 47,XY,+mar [100%] r(4) all available centromeric probes Amniocentesis due to ultrasound-result: alobar holoprosencephaly, pregnancy terminated {7} case A {11} case 1  
  04-
CW-2
female/
4y
PBL de novo 47,XX+mar[16%]/
46,XX[84%]
r(4) SKY; telomeric probes  see below {9; 10}  
At birth length: 51cm; at 4y non-specific dysmorphic features and mild mental retardation plus no speech;; at 11y she underwent a scoliosis fusion level D5-L1 due to dextro-convex thoracal scoliosis; at age of 10 y IQ 80, later on she could follow normal school education. At 22 she was a phenotypically normal female except for macrosomia (length 183cm).
  04-
CW-3
female/
prenatal
AF de novo 47,XX+mar[100%] r(4) different FISH probes (D4Z1; wcp4) see below {4} case 16
{5} case  1
 
Fetal pathology detected in ultrasound due to advanced maternal age; alobar holoprosencephaly confirmed after termination
  04-
CW-4
female/
n.a.
n.a. n.a. 47,XX,+r[30]/
46,XX[20]
r(4) SKY dysmorphic features, more prominent on the right {6} case MP3  
  04-
CW-5
male/
14y
PBL n.a. 47,XY,+mar[100%] min(4)(:p1?5→q11.1:) cenM, subcenM mental retardation (oligophrenia), growth retardation, strabismus, upward slant to the eyes, high-arched palate, abnormal teeth positioning {0} provided by Dr. Iourov, Moscow, Russian Federation  
                     

 

 


References

Cases with unclear clinical correlation (U)

 

 
  case no. gender/
age at diagnosis
studied
material
de novo/
inherited
GTG-banding result
grade of mosaicism
final result of the sSMC test
methods
clinical symptoms reference  
  04-
U-1
male/
1m
PBL de novo 48,XY,+21,+mar[28]/
47,XY,+21[7]
min(4)(:p12q11:) 
partial maternal iso-UPD 4p16:
cenM
subcenM; UPD-test
Down-syndrome  {1} case 10
{2; 41}
 
  04-
U-2
male/
2y
PBL
cell line at ECACC DD1329
de novo 47,fra(X)(q27.3)Y,+mar[8]/
46,fra(X)(q27.3)Y[42]
mar(4).ish(cep+;wcp-) all centromeric probes; wcp 4 see below {12} case 3  
no physical abnormalities at 2y but language and other development moderately delayed; fragile X syndrome
  04-
U-3
male/
prenatal
AF de novo 47,XY,+mar[10]/
46,XY[9]
inv dup(4)(:p11.1q12:) cenM
subcenM; UPD-test
Amniocentesis due to advanced maternal age; no ultrasound abnormalities; pregnancy terminated  {1} case 9  
  04-
U-4
female/
prenatal
Amnion
cell line at ECACC DD0068
de novo 47,XX,+mar[27%]/
46,XX[73%]
min(4) all centromeric probes; wcp 4; UPD-test see below {3} case 3
{15} case 2
 
Amniocentesis due to advanced maternal age; pregnancy terminated; mar present in fetal tissue, no clinical details available on fetus
  04-
U-5

see mult 2-18

{24} case MK
{25} case 15
 
  04-
U-4
female/
prenatal
Amnion
cell line at ECACC DD0068
de novo 47,XX,+mar[27%]/
46,XX[73%]
min(4) all centromeric probes; wcp 4; UPD-test see below {3} case 3
{15} case 2
 
Amniocentesis due to advanced maternal age; pregnancy terminated; mar present in fetal tissue, no clinical details available on fetus
  04-
U-6
female/
prenatal
AF de novo 47,XX,+mar[20]/
46,XX[13]
r(4)(::p11q11:) centromeric probes see below {21} case 35  
Amniocentesis due unclear mental retardation of brother of father of the child. Normal ultrasound; termination of pregnancy, in autopsy no anomalies.
  04-
U-7
male/
newborn
PBL de novo 47,XY,+mar[100%] r(4)(::p11q12::)[8]/
r(4;4)(::p11
q12::p11q12::)[2]
cenM; subcenM see below {0} provided by Dr. A. Dufke, Tübingen, Germany  
cerebellar atrophy, agranulocytosis, lymphocytosis; Hematuria, developmental delay ; cobalamnin-C-defect (homozygote  c271dupA mutation in MMACHC gene in 1q34.1)
  04-
U-8
male/
n.a.
PBL de novo 47,fra(X)(q27.3)Y,+r[30]/
47,fra(X)(q27.3)Y[70]
r(4)(::p14p13::p10 q10::q31.1q31.3::) all centromeric probes; wcp 4; midi; YAC probes as specified in {13} see below {13} case A
{14} case19
 
moderate mental retardation; , minor anomalies, like macrocephaly, plagiocephaly, brachycephaly, epicanthic folds, flat midface with relative prognathism, malocclusion, high arched palate, hypoplastic ala nasi, thin upper lips, short and broad neck, small hands and feet; fragile X-syndrome.
  04-
U-9
female/
prenatal
AF n.a. 47,XX,+mar[100%] min(4)(:p11q11:) cep probes, BACs {see 35} MLPA advanced maternal age {35} case 2  
  04-
U-10
female/
1y
PBL n.a. 47,XX,+mar[100%] der(4)t(4;7)(q12;p22.1)
array-data: break on #4 position 52.38 and #7 position 7.06
diff. FISH-probes; aCGH Plagiocephaly, optic nerve hypoplasia, hearing loss, hip dysplasia, and short stature. {38} case 1
{42}
 
  04-
U-11
female/
newborn
PBL mat
t(4;9)
47,XX,+mar[100%] der(4)t(4;9)(q12;p21.2)
array-data: break on #4 position 54.42 and #9 position 27.24
diff. FISH-probes; aCGH severe physical clincal signs; child died with 8 months {39; 42}  
  04-
U-12
n.a./
postnatal
PBL n.a. n.a. mar(4)(:p13q12:)
hg19:44.45–57.26Mb
also (partial) (i)UPD 4
aCGH most likely dymorphic and MR {44} 1 case  
  04-
U-13
male/
prenatal
AF n.a. 47,XY,inv(16)(q12q24),+mar[100%] min(4)(:p11q12:)

cenM/
subcenM

n.a. {0} provided by Dr. Stumm, Berlin, Germany  
                     

 

 


References

Cases with neocentromeres (N)

 

 
  case no. gender/
age at diagnosis
studied 
material
de novo/
inherited
GTG-banding result
grade of mosaicism
final result of the sSMC test
methods
clinical symptoms reference  
  04-N-
 q22.1/
 1-1
see McCl-04-N-q22.1/1-1

{16; 18; 19; 27}

 
                     

 

other 2 neocentromere 4 cases (no sSMC):

Warburton PC, Barwell J, Splitt M, Maxwell D, Bint S, Ogilvie CM.
Class II neocentromeres: a putative common neocentromere site in band 4q21.2.
Eur J Hum Genet. 2003;11(10):749-753.
Amor DJ, Bentley K, Ryan J, Perry J, Wong L, Slater H, Choo KH.
Human centromere repositioning "in progress".
Proc Natl Acad Sci U S A. 2004;101(17):6542-6547.

 

N-Cases with similar imbalances NOT caused by sSMC (N-IMB):


 
  case no. gender/
age at diagnosis
studied
material
de novo/
inherited
GTG-banding result and FISH result incl. grade of mosaicism test
methods
clinical symptoms reference  
 

04-N-
IMB-
p/ter
many

dup 4p; 75 cases summarized in {30}

{30; 32}