- sSMC -CHROMOSOME 4
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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 |
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the probably non-dosage sensitive pericentric region of chromosome 4
SCHEMATIC CYTOGENETIC DEPICTION
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 |
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)(:p13→q13.1:) 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)(::p12→q13.1::) ~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)(::p12→q13.1::) |
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)(:p11→q12:) |
cenM, subcenM | normal male, infertile | {45} case 4-2 |
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| 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)(:p11→q11:) | 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)(::p11→q13.1::) |
cenM, subcenM; 1Mb-probeset |
mentally normal female, studied after abortion, (also present: overgrowth; macrocephaly; diabetes) |
{0} provided by Drs Wagner and Stibbe, Hannover, Germany. | ||
| 04-O- p11/ 4-1 |
female/ prenatal |
AF | pat (low mosaic; sib also with sSMC) | 47,XX,+mar[100%] |
min(4)(:p11→q12: |
aCGH; locus specific FISH; | father normal, sib normal, normal child born | {46} | ||
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 | ||
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)(pter→q10:) | 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?5→q12:) | 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)(:p14→q11.1:) 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 |
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| 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?12→q?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. |
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| 04-W- p12/ 2-2 |
male/ 4y |
PBL | de novo | 47,XY,+mar[8]/ 46,XY[42] |
min(4)(:p12→q12:) | 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)(::p12→q13.2::)* 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)(::p12→q13.2::) 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)(:p11→q11:) | 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)(:p11→q12:) 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)(:p11→q12:)[9]/ min(4)(:q12→p11: :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)(:p11→q12:) array: 52.38-54.86 |
aCGH | see below | {40} case 5 |
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| TOP; Dysmorphic features: hypertelorism, long philtrum |
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| 04-W- p10/ 1-1 ° |
male/ 27y |
PBL | de novo | 47,XY,+r[100%] | r(4)(::p10→q12::) | 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)(:p10→q13:) (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 |
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| 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 | ||
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)(:p12→q11:) partial maternal iso-UPD 4p16: |
cenM subcenM; UPD-test |
Down-syndrome | {1} case 10 {2; 41} |
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| 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)(:p11.1→q12:) | 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 |
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| Amniocentesis due to advanced maternal age; pregnancy terminated; mar present in fetal tissue, no clinical details available on fetus | ||||||||||
| 04- U-5 |
{24} case MK {25} case 15 |
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| 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 |
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| 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)(::p11→q11:) | 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)(::p11→q12::)[8]/ r(4;4)(::p11→q12::p11→q12::)[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)(::p14→p13::p10→ q10::q31.1→q31.3::) | 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)(:p11→q11:) | 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)(:p13→q12:) 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)(:p11→q12:) |
cenM/ |
n.a. | {0} provided by Dr. Stumm, Berlin, Germany | ||
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} |
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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- |
dup 4p; 75 cases summarized in {30} |
{30; 32} | |||||||