FISH

SMALL SUPERNUMERARY MARKER CHROMOSOMES

- sSMC 6 -

           References

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 6   maternal   paternal   unclear


the probably non-dosage sensitive pericentric region of chromosome 6

 


SCHEMATIC CYTOGENETIC DEPICTION                    
  sSMC-6DISCLAIMER

 


 

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], * case mult 2-39

 critical region ? --- 57.35* uncritical region   [58.40 centromere 63.40]   uncritical region 66.40* --- 65.20 critical region

Below adapted for UCSC hg19, 2009

 critical region ? --- 57.15 uncritical region   [58.70 centromere 63.30]   uncritical region 66.3 --- 65.08 critical region

 DISCLAIMER


 Clinical symptoms of centromere-near proximal imbalances

 

chromosomal region

6p - proximal

6q - proximal

symptoms

brain malformations

(50 %) 0 %

developmental delay

(50 %) 50 %

dysmorphic face

(100%) 100 %

genital abnormalities

0 % 50 %

heart defect

0 % 50 %

hyperpigmentation (streaky)

(50 %) 0 %

hypotonia

0 % 50 %

macrocephaly

0 % 25 %

mental retardation

(50 %) 50 %

macrocephaly

0 % 25 %

microcephaly

(100%) 0 %

vision impaired

0 % 50 %
number of cases (marked with “°” below) 2 4



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  
  06-O-
p22.3/
1-1
see McCl-06-O-p22.3/1-1 {12}
{32} case 10
 
  06-O-
p12/

1-1 
female/
prenatal
AF, chord blood de novo 47,XX,+mar[74%]/
46,XX[26%]
in chord blood mar in 87%
min(6)(:p12q11:) all centromeric probes; wcp 6, RX-FISH at 4y child normal {20} case 2  
  06-O-
p11.2~
p11.1/
1-1 
see McCl-06-O-p11.2~p11.1/1-1  {0} provided by Dr. Spranger, Bremen, Germany)  
  06-O-
p11.1/

1-1
female/
prenatal
AF de novo 47,XX,+mar[26]/ 46,XX[5] min(6)(:p11.1q11.1:)
no euchromatin on sSMC detectable
cenM, subcenM
and probes in {15}
array-CGH;
UPD-test
Advanced maternal age; no ultrasound abnormalities; normal child born in gestational week 39+6 {16}case 6-2
{15} case 38
{0}
{39} case Sm-2
 
  06-O-
p11.1/

2-1
male/
35y
PBL
(EKF-
cellbank)
n.a. 47,XY,+mar[100%] dic(6;6)(:p11q11::p11q11:) cenM, subcenM fertility problems {0} provided by Prenatal Genetics, Barcelona, Spain  
                     

 

O-cases with unclear/insufficient characterization of the sSMC itself (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  
  06-
CO-1
female/
prenatal
AF maternal
(no info on mosaic status)
47,XX,+r[?]/
46,XX[?]
r(6).ish(D6Z1+) FISH with all available centromeric probes normal at 5m; mother clinically normal {8}  
  06-
CO-2
male/
prenatal
AF, PBL de novo 47,XY,+mar[6]/
46,XY[10]
in PBL mar in 8 of 20
r(6) .ish(cep+;wcp6+)
aCGH: no result
all centromeric probes; wcp 6, aCGH
at 9 months child normal, grossly normal at 2y {11} case 2
{21} case 57
{34} case 2
 
                     

 


References

Cases with clinical findings (W)

 

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  
  06-W-
p21.2/
1-1
moved to 06-U-8 {1} case 5
{2}
{9} case 5
 
  06-W-
p21.2/
2-1
female /
prenatal
AF, PBL  de novo 47,XX,+mar[12]/
46,XX[3]
in PBL mar in 15 of 20
r(6)(::p21.2q11.2::)
aCGH: CT-2118F18 and RP11-43B19 still present on the sSMC

 
all centromeric probes; wcp 6; aCGH
 
see below {11} case 1
{21} case 56
{34} case 1
 

 
at birth postnatal height, weight and OFC <<5%, feeding difficulties, hydronephrosis, deviated septum, mild dysmorphic features, small for gestational age, developmental delay, epilepsy, mild dysmorphic features
  06-W-
p21.1/
1-1   °
male/
1m
PBL de novo 47,XY,+mar[13]/
46,XY[7]
min(6)(:p21.1q11:)*
sSMC derived from a normal maternal chromosome 6
SKY;  CGH; UPD-test see below  {13; 22}  
normal pregnancy, birth weight at 50th centile, and OFC at 10th centile due to premature fusion of cranial sutures - brachycephaly with mild plagiocephaly. At 18 m height and weight >50th centile; microcephaly, midface hypoplasia, advanced dentations, swirling pigmentary streaks in several skin areas - showing similar distribution like Blaschko lines in several areas; hyperactivity, language delay, normal motor development; at 2y 8m height 93cm (50th centile); weight 15.1kg (75-90th centile) OFC 46cm (3rd centile). Now still brachycephaly and round flat face with midface hypoplasia, unusually shaped ear tragus and thin upper lip. Mild psychomotor development delay. IQ borderline; increased activity, distractibility, poor attention span - hyperactivity (suggested ADHD). MRI at 2y detected global reduction of brain volume but no specific brain anomalies.
  06-W-
p12.3/
1-1
male/
16y
PBL n.a. 48,XY,+mar,+mar[8]/
47,XY,+mar[10]/
46,XY[3]
see below  cenM;
subcenM; MCB; aCGH
delayed language and psychomotor retardation {38} case 4
 
r(6)(::p12.3q12::)[2]/r(6)(::p12.3q12::)x2[5]/min(6)(:p12.3q12:)[9]/ min(6)(:p12.3q12:)x2[2]/
min(6)(:p12.3
q1?2::q1?2p12.3:)[1]/r(6)(::p12.3q12::),r(6;6)(::p12.3q12::p12.3q12::)[1]
variant size acc. to BAC-FISH: 57.3-65.2MB and 48.8-63.4 MB; aCGH: 51.55-66.71
  06-W-
p11.2/
1-1  °
male/
16y
PBL n.a. 47,XY,+mar[60%]/
46,XY[40%]
see below  cenM/
subcenM; aCGH
Lymphangiomatose of the skeleton plus mild facial dysmorphism and a relative microcephaly {38} case 4
{39} case Sm-3
 
min(6)(:p11.2q11.1:)[92%]/invdup(6)(:q11.1p11.2::p11.2q11.1:)[8%]; aCGH: 57.09-64.11
  06-W-
p11.1/
1-1   °
male/
2y
PBL
(EKF-
cellbank)
de novo 48,XY,+marx2[59]/
47,XY,+mar[25]
46,XY[40]
min(6)(:p11.1q12:)* different FISH probes, micro satellite analysis; UPD-test see below {7} case 2
{18}
{23} case 4
 
Born at term by vaginal delivery after an uneventful pregnancy; birth weight 3150g (25th centile), length 56cm (90-97th centile), OFC 36cm (90-97th centile). APGAR 7 and 9 at 1 and 5 minutes, respectively. Congenital heart defect (VSD, PDA), muscular hypotonia, bilateral cryptorchidism, hypoplastic genitalia, mild dysmorphic facial features, such as mild hypotelorism, elongated philtrum, and thin lips. At age of six months VSD was operated successfully. PDA closed spontaneously in the first months of age. Corrective surgery for undescended testes, detected in the inguinal canals, carried out at the age of three years; operation was ineffective as the cryptorchidism relapsed after a couple of months. Psychomotor development retarded; sitting at 12 m, walking at 20 m, speech (first words) at 2 y (first sentences) at 5.5y. He lisps and speaks indistinctly. Logopaedic examination indicated labial and lingual dyslalia. manual skills are weak. He is left-handed and writes right-to-left. Some of the letters resemble a mirror reflection of the correctly written letters. Now, at the age of 9, he can write only single words: problems with longer concentration on a particular activity. The auditory and visual memories are poorly developed. Psychological examination showed an IQ of 56. Ophthalmologic examination revealed alternating convergent strabismus and binocular hypermetropia. At 9y: weight 46 kg (90-97th centile), height 135cm (50th centile) and OFC 56.5cm (above 97th centile). Mild dysmorphic features are noticeable, i.e. coarse face, thin upper lip and low posterior hairline border. The patient has small, hypoplastic penis and scrotum, flat feet with bilateral valgus first toes
  ***
06-W-
p11.1/
2-1   °

***
female/
12y
PBL
(EKF-
cellbank)
n.a. 47,XX,+mar[17]/
46,XX[3]
see below cenM, subcenM
aCGH
abnormal aggressive behavior, deep sitting ears, very slim {38} case 6
{0}
 
min(6)(:p11.1q13:)[5]/r(6)(::p11.1q13::)[2]/r(6)(::p11.1q13::p11.1q13::)[2]/r(6)(::p11.1q13:
:p11.1
q13::p11.1q13::p11.1q13::)[1]/inv_dup(6)(:p11.1q13::p11.1q13:)[10]; 
BAC-FISH: 58.4-65.2MB aCGH 62,765,543-72,341,212 MB
                     

 

 

 

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  
  06-W-
IMB-
p21.3/
1-1
male/
newborn
PBL de novo 46,XY,dup(6)(p12p21.3) wcp 6 see below {34}  
cerebellar hypoplasia, dilated cerebral ventricles, choanal atresia, cloudy cornea, multiple minor abnormalities, developmental delay, died at 16 m
  06-W-
IMB-
p12.1/
1-1 and
1-2
 female + male/
postnatal
PBL paternal
(balanced)
46,XX,der(12)(12pter12q21.33::6p12.16p22.1::12q21.3312qter) dir ins(12;6) pat n.a. see below {26} two cases  

case 1: born by spontaneous vaginal delivery at the 40th week of a pregnancy with no remarkable elements. Few days after birth presence of several craniofacial dysmorphism associated with anal atresia. birth weight 2900 g (<50th percentile), length 47 cm (<25th percentile) head circumference 32 cm (<25th percentile). During the perinatal period respiratory distress with frequent cyanotic attacks and recurring respiratory infections, and feeding difficulties; slight general hypotonia. At 5 months: growth retardation, microcephaly, prominent occiput, narrow forehead, hypertrichosis and low hair line, close-set eyes, short palpebral fissures, long eyelashes, abnormally modeled ears, wide nasal bridge, bulbous nose with anteverted nares, long and prominent philtrum, small mouth with thin lips and micrognathia. At 2-1/2 years, her weight is 7 kg and height 77 cm, both values under 3rd percentile, her psychomotor development is severely delayed.
case 2: First cousin of case 1's father. The reproductive history reported two miscarriages, a girl born at term with several malformations, who died at 3 months, a girl born healthy, still living, and finally the baby we report.: born at full term, birth weight 2800 g, head circumference 34 cm (<50th percentile), abnormal sutures, absence of anterior fontanels, capillary angioma on forehead, small palpebral fissures, epicanthus, wide nasal bridge, bulbous nose, small mouth with thin lips, micrognathia, abnormally modeled ears, short limbs, overlapping fingers, talipes, bilateral hydrocele, phimosis, hypertonia, opisthotonus. Feeding problems and respiratory distress were also reported. This infant died at the age of 8 months, probably of pneumonia.

  06-W-
IMB-
q11/
1-1
 n.a./
postnatal
PBL de novo 46,dup(6)(q11q15) wcp 6 craniofacial dysmorphism, psychomotor retardation, cryptorchidism and hypospadias {31}  
                   

 

W-cases with unclear/insufficient characterization of the sSMC itself (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  
  06-
CW-1
male/
35y
according to {1;9} cell line at ECACC DD1329; which is obviously incorrect de novo 47,XY,+mar[29]/
46,XY[21]
r(6) .ish(cep+;wcp6+) all centromeric probes; wcp 6; UPD-test see below {1} case 4
{9} case 4
 
severe mental retardation, seizures, dysmorphic; at 35y he has fits and shows no social behavior; thick lips with lower lip everted, scoliosis, truncal obesity, soft skin, lax joints, thick tapering fingers
  06-
CW-2
moved to 06-W-p21.2/2-1 {11} case 1
{21} case 56
{34} case 1

 
  06-
CW-3
male/
32y
PBL  de novo 48,XXY,+mar[30]/
47,XXY[20]
mar(6) .ish(cep+) all centromeric probes see below {35, 41}  
Klinefelter syndrome; growth retardation at birth and at 8m of age
                   

 

 

 


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  
  06-
U-1
see mult 2-3   {3}  
  06-
U-2
see mult 2-4   {4} case 3  
  06-
U-3
see mult 2-5   {5} case 7  
  06-
U-4
see mult 2-10   {6}  
  06-
U-5
 male/
16y
PBL ?paternal? 
mar in 5/105 cells
47,XY,der(6)(pter→q22.3::q22.3→ q16.1::q221.1→qter),+mar min(6)(:q11.1q11.2:)
aCGH: p11.2
q12 57,313,842-66,709,997 MB
midi
aCGH
psychomotor retardation, dwarphism with scoliosis {0} provided by Dr. A. Dufke,
Tübingen, Germany
 
  06-
U-6
see mult 2-19      
  06-
U-7
 female/
prenatal
AF n.a. 47,XX,+mar[35]/
46,XX[45]
min(6)(:q11.1q11.1:)
aCGH: no euchromatin detected
cenM, subcenM
aCGH
n.a. {0} provided by Dr. Mehnert, Neu-Ulm, Germany  
  06-
U-8
female/
1m
PBL
cell line at ECACC DD1261
de novo 47,XX,+r[37]/
46,XX[13]
r(6)(::p21.2q10)*
paternal UPD 6
all centromeric probes; wcp 6; midi; UPD-test see below  {1} case 5
{2}
{9} case 5
 
IUGR in week 35; Birth by cesarean section in  week 38; Birth weight 1,8kg, APGAR 6/8/-; protuberant tongue; slightly prominent clitoris and anteriorly placed anus, small umbilical hernia; transient neonatal diabetes; smiling at 6m, sitting at 7.5m, standing with support 1y; At 2y8m epicanthic folds, thicker upper lip and prominent cheeks; 
  06-
U-9
 female/
prenatal
AF n.a. 47,XX,+mar[19]/
46,XX[11]
mar(6)(:p11.2q12:)
aCGH: 57.58-65.72 MB
aCGH abnormal biochemistry; TOP; no external abnromalities
{40} case 8  
                     

 


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  
  06-N-
q16.2/
1-1
see McCl-06-N-q16.2/1-1 {16; 24; 25}  
  06-N-
qt26/
1-1
n.a./
prenatal
AF de novo 47,+mar[60%]/
46[40%]
mar not in fetal blood but in placenta
inv dup(6)(qterq26:
:q26
qter)*
all centromeres, wcp probes, sub-telomere 6q see below {14; 25}  

sSMC detected in week 16 of gestation; baby born at 41 week of gestation; APGAR 10/10) at two years normal psychomotor development, microcephaly, mild hearing loss.

                     

see as well for neocentromere of chr. 6 Ref {36}

 

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  
  06-N-
IMB-
p2?/
1-1 to
7-1
7 cases with partial trisomy of 6pter; see also {33} {27-30}{33}