FISH

SMALL SUPERNUMERARY MARKER CHROMOSOMES

- sSMC 13 -

Cases without clinical findings	2	Cases with clinical findings	3	symptoms
Cases with unclear clinical correlation		Cases with neocentromeres	19	tumor 0

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 13 maternal paternal unclear

the probably non-dosage sensitive pericentric region of chromosome 13

SCHEMATIC CYTOGENETIC DEPICTION
sSMC-13 DISCLAIMER

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]

[p-tel --- centromere 18.40] uncritical region 19.31 --- 22.29 critical region

Below adapted for UCSC hg19, 2009

[p-tel --- centromere 19.50] uncritical region 20.41 --- 23.42 critical region

DISCLAIMER

Clinical symptoms of centromere-near proximal imbalances

chromosomal region	13q - proximal
symptoms	13q - proximal
no informative case	-
number of cases (marked with “°” below)	0

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
* 13-O- q11.2/ 1-1 *	female/ prenatal	AF	de novo	47,XX,+mar[100%]	min(13)(pter→q11.2:) FISH-data: present at least up to 19.31 MB	cenM; subcenM	Advanced maternal age; normal child at 10 months of age	{0} provided by Dr. Sagi, Jerusalem, Israel
13-O- q12.2/ 1-1	female/ prenatal	AF/ PBL	de novo	47,XX,der(13),+mar[100%]	47,XX,dic(13)(pter→q12.2: :p11.2→qter), +min(13)(pter→q12.2: :p1?2→pter)	cep probes, subcenM	Aberrant first trimester screening, normal child born and normal at 1 y	{0} provided by Dr. Prager and Junge, Dresden, Germany

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
13-W- q12.12/ 1-1	female/ postnatal	PBL?	n.a.	47,XX,+mar[100%]	min(13)(pter→q11.12:)	array-CGH	abnormal	{43} case 27105
* 13-W- q12.12/ 1-2 *	female/ 11y	PBL?	n.a.	47,XX,+mar[100%]	min(13)(pter→q12.12:) aCGH: break in 22.29 MB	different FISH-probes; array-CGH	Agenesis of the corpus callosum, scoliosis, sleep apnea, obesity	{50} case 8
13-W- q13.2/ 1-1	n.a./ prenatal	AF	de novo	47,+mar[100%]	mar(13)(pter→q13.2:)* size ~14MB = position 32.40	n.a.; subcenM with 3 BACs	see below	{24} case 14
13-W- q13.2/ 1-1	Multiple anomalies noted on prenatal ultrasound, including diaphragmatic hernia, open neural tube defect, micromelia, abnormal skull, and single umbilical artery; pregnancy terminated.							{24} case 14

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
13-W- IMB- q12/ 1-1 to 1-5	female and male/ postnatal	PBL	maternal (balanced translocations)	der(13)t(13;div. chrs.)(q12;div. breakpoints)	n.a.	see below	{32-37} reviewed in {38}
13-W- IMB- q12/ 1-1 to 1-5	features in common: short stature, microcephaly, dysplastic ears, strabismus, epicanthic folds, down slanting palpebral fissures, short mandible, mental retardation form mild to severe.						{32-37} reviewed in {38}
13-W- IMB- q13/ 1-1 to 1-2	female and male/ postnatal	PBL	maternal (balanced translocations)	der(13)t(13;div. chrs.)(q13;div. breakpoints)	n.a.	similar to 13-W-IMB-q12 cases	{37; 39} reviewed in {38}

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
13- U-1	female/ 10m	PBL	de novo	47,XX,inv dup(13)(qter→q21::q21→qter),+del(13)(q21)[100%]	del(13)(q21)	probes as specified in {9}	see below	{8} case 13b {9; 12}
13- U-1	low birth weight, brachycephaly, microcephaly, thick eyebrows and curly eyelashes, bil. microphtalmia, developmental delay, bil. postaxial polydactyly							{8} case 13b {9; 12}
13- U-2	male/ 1w	PBL	de novo	47,XY,inv dup(13)(qter→q14.1:: q14.1→qter), +mar1[75%]/ 47,XY,inv dup(13)(qter→q14::q14→qter), +mar2[25%]	mar1 = r(13)(::p13→q14.1::) mar2 = r(13)' (::p13→q14.1: :p13→q14.1::)	RB1 probe; probe in 13q32-q33; cep13/21;	see below	{5; 12; 25} {8} case 13a
13- U-2	normal birth and delivery; weight at 25. centile, flat philtrum, slightly protuberant ears, capillary hemangiomas on forearm, hypospadias, hypotonic; at 4m HC at 25. centile, length at 75. centile, interpupillary distance at 85. centile; bilateral congenital glaucoma, bilateral retinoblastoma, no hearing at right ear, developmental delay at 17m;							{5; 12; 25} {8} case 13a
13- U-3	see mult 2-2							{1}
13- U-4	chimera/ prenatal	skin fibroblasts	maternal mother has 48,XX,+mar 2x	chi46,XYpat[18]/47,XX,+mar1[8]	inv dup(13)	FISH - probes not specified	see below	{1}
13- U-4	Twin A - placenta grossly enlarged and cystic, low amniocytes fluid, poor growth; at 15 w spontaneous abortion; second twin was normal, but also aborted.							{1}
13- U-5 to U-6	male and female/ n.a.	n.a.	de novo	47,+mar[100%]	mar(13)	wcp13	n.a.	{186}cases 23-24
13- U-7	male/ child	n.a.	n.a.	47,XY,+mar[40]/ 46,XY[10]	min(13)(pter→q12.1:)	cenM; subcenM	n.a.	{0}case provided by Dr. Saigi, Israel
13- U-8	male/ 6y	PBL	maternal balanced translocation	47,XY,+mar[100%]	der(13)t(8;13) (p23.1;q12.11) array-CGH: chr. 8: 0-7.09 MB chr. 13:17.92-21.81 MB	cenM; subcenM, midi, subtel 8p, array-CGH	see below	{0}case provided by Dr. Kistner {Schwerin, Germany}
13- U-8	mental retardation, general developmental delay, severe retardation in language development; no family history; 6 healthy sisters and brothers							{0}case provided by Dr. Kistner {Schwerin, Germany}
13- U-9	see mult 2-26							{0} case provided by Dr. Michal Sagai, Israel
13- U-10	male/ 2y	PBL	de novo	48,XY,+mar1,+mar2[20]	min(13)(qter→q33.3: :p12→q12.12:) mar 2 not defined	array CGH, BACs acc. to {28}	see below	{28}case 2
13- U-10	moderate global developmental delay, bilateral anterior segment dysgenesis of the eye in the form of the Axenfeld-Rieger anomaly, macrocephaly, past history of bilateral inguinal hernias, and several depigmented maculae. An MRI was significant for a short, thick corpus callosum, prominent perivascular spaces with thinning of the gray matter, and an enlarged posterior fossa.							{28}case 2
13- U-11	n.a./ n.a.	n.a.	n.a.	47,+mar[?%]	mar(13)	wcp probes	no info available	{45} 1 case
13- U-12	male/ adult	PBL	n.a.	48,XY,+21,+mar[1]/ 47,XY,+21[29]	r(13)(::p1?2→q1?3::)[1]/ der(13(pter→q?12.11: :p11.1→q1?3: :q11.1→p1?1.2:)[2]	cenM, subcenM	Down syndrome	{0} provided by Dr. Brecevic, Zagreb, Croatia
13- U-13	female/ prenatal	AF	de novo	47,XX,+mar[100%]	min(13)(:p12→q12.1:)[3]/r(13)(::p12→q12.1::)[7]	cenM, subcenM	no info available	{0} provided by Dr. Müller-Navia, Mainz, Germany
13- U-14	female/ prenatal	AF	maternal balanced translocation	47,XX,+mar[100%]	der(13)t(4;13)(q31.3;q13)	n.a. MLPA	sonographic abnormalities (polyhydramnion, unilateral hydrothorax)	{47}case 7
13- U-15	female/ prenatal	CH; AF	n.a.	CH: 47,XX,+13[12]/ 47,XX,+mar[8]/ 46,XX[30] in AF: 47,XX,+13[70%]/ 46,XX[30%]	inv dup(13)(q12.11)	subcenM	sonographic abnormalities pointing towards trisomy 13; TOP	{0} provided by Dr. Petersen, Athens, Greece
13- U-16	female/ newborn	PBL	n.a.	47,XX,+mar[100%]	der(13)t(1;13)(q32;q12) array-CGH: chr. 1: 208.03 to qter chr. 13: pter to 24.40 Mb	aCGH	different health problems and developmental delay	{0} case analyzed by GENZYME; provided by parents

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
13- N-1	n.a./ prenatal	AF	de novo	47,+mar[100%]	inv dup(13)(qter)	wcp	nuchal translucency and measurements above 90th centile. TOP, no further information available	{31}
13-N- p12.3/ 1-1	see McCl-13-N-p12.3/1-1							{48}
13-N- qt21/ 1-1	female/ prenatal	AF	de novo	47,XX,+mar[3]/ 46,XX[36]	inv dup(13)(qter→q21: :q21→qter) sSMC derived from maternal chromosome 13	wcp 13, QF-PCR	TOP; round facies, hypertelorism, down-slanting palpebral fissures and a bifid nasal bridge.	{49}
13-N- p21.31/ 1-1	see McCl-13-N-p21.31/1-1							{3; 16; 25; 26; 42}
13-N- qt31/ 1-1	female/ 4y	PBL	de novo	47,XX,+mar[54%]/ 46,XX[46%]	inv dup(13)(qter→q31: :q31→qter)	different FISH probes as specified in {4}	see below	{4} case 1; {12} {14; 16; 25; 27}
13-N- qt31/ 1-1	at birth weight and OFC <3. centile; at 4y OFC normal but weight at 97. centile; additionally mild convergent strabismus, bitemporal narrowing, hypertelorism, clinodactyly 5. finger; 2/3 syndactyly of feet.							{4} case 1; {12} {14; 16; 25; 27}
13-N- qt31/ 1-2	male/ 4y	PBL	de novo	47,XY,+mar[60%]/ 46,XY[40%]	inv dup(13)(qter→q31: :q31→qter)	midi; different FISH probes as specified in {8}	see below	{8} case 13e {10} case 2; {12; 16; 44}
13-N- qt31/ 1-2	normal growth, thick eyebrows and hypertelorism, strabismus, deformed lobes, mild mental retardation ; seizures; excess teeth; PDA; diaphragmic hernia, bronchial anomalies, intestinal malrotation, scoliosis, hypospadias							{8} case 13e {10} case 2; {12; 16; 44}
13-N- qt31/ 1-3	female/ 7y	PBL/ skin fibroblasts	de novo	blood and fibro: 47,XX,+mar[13%]/ 46,XX[87%]	inv dup(13)(qter→q31: :q31→qter)	all centromeric probes; cosmids for 13q14.2, 13q32-33, 13qtel; CGH	see below	{13; 16; 25}
13-N- qt31/ 1-3	born at 36 weeks gestation after a normal pregnancy; weight 2.9 kg, treated for jaundice with 1 day of phototherapy; mild motor developmental delay. She sat at 8months, crawled at 10 months, stood up at 1 year, and walked at 18 months. She was able to say ‘‘mummy’’ and ‘‘daddy’’ at 9 months, and knew a series of words at 18 months. At 7y presence of soft dysmorphic features, concerns about her behavior and progress at school, torticollis present from birth, reported but unconfirmed left-sided hearing loss and parentally-described hyperactivity at school. Previous dental examination had revealed the presence of a complete extra set of teeth. At school, she interacted well with the other children and was in the correct year for her age, but did have extra lessons for mathematics and reading. On examination, her occipitofrontal circumference was 54 cm (98th centile), her weight was 32 kg (90th centile), and height 128.2 cm (75-90th centile). She had bilateral epicanthic folds, a long smooth philtrum, a large fleshy left earlobe, and right torticollis. She was noted to be asymmetrical and her right arm diameter was 1 cm larger than the left. She also had pes planus. There was no evidence of any neurological deficit and her gait was normal. Following she developed episodes reminiscent of absence seizures. During these episodes she was noted to stare vacantly into space for up to a minute. The EEG showed generalized spike and slow wave discharges confirming primary generalized epilepsy. She was started on sodium valproate. Investigations showed that she had small thoracic ribs bilaterally. A renal ultrasound was normal.							{13; 16; 25}
13-N- qt31/ 1-4	female/ prenatal	AF/ PBL	de novo	47,+mar[?%]/ 46[?%]	inv dup(13)(qter→q31: :q31→qter)	CGH, cep probes, wcp probes, subtelomere probes	see below	{18, 20, 21, 30}
13-N- qt31/ 1-4	amniocentesis in week 24 due to suspect ultrasound with large cisterna magna, no renal differentiation, hypotelorism and ventriculomegaly; TOP; autopsy confirmed facial dysmorphism and renal dysplasia							{18, 20, 21, 30}
13-N- qt31/ 1-5	male/ 3m	PBL	de novo	47,XY,+mar[100%]	inv dup(13)(qter→q22.3~31.1: :q22.3~31.1→qter)	M-FISH subtelomere probes; MCB	see below	{23}case Neo #13-6
13-N- qt31/ 1-5	Born at term by cesarean section after uneventful pregnancy. Birth weight 3600 g, birth length 49 cm. At 3-months developmental delay, poor sucking; weight 5660g (25-50th centile), length 62 cm (25-50th centile) head of circumference (OFC) 40.3 cm (25-50th centile); Hemangiomas in frontal region, pit on right ear helix, hypertelorism, left epicanthal fold, broad and flat nasal bridge, bulbous nasal tip, anteverted nares, long philtrum, mild micrognathia, wide anterior fontanel, broad thumbs, toe syndactyly. Abdominal ultrasonography and echocardiography were normal; cranial CT → Dandy-Walker variant, arachnoid cyst at temporal lobe posteromedial region, porencephaly at left caudate nucleus and frontal white matter; cerebellar vermis dysplasia: broad fourth ventricle, mega cisternae magna, mild cortical cerebral atrophy. Cerebral mild dysmyelinization.							{23}case Neo #13-6
13-N- q31.1/ 1-1	see McCl-13-N-q31.1/1-1							{15; 25}
13-N- qt31.1/ 2-1	male/ prenatal	AF	de novo	47,XY,+mar[100%]	inv dup(13)(qter→q31.1: :q31.1→qter) array: size 32.9 MB	arrayCGH	see below	{51}
13-N- qt31.1/ 2-1	at 12 weeks estimated gestational age (EGA) cystic hygroma and IUGR; At 14 and 17 weeks EGA still IUGR, short long bones, persistant cystic hygroma, mega cisterna, cerebellar hypoplasia, hyperechogenic and large kidneys. TOP at 17 weeks EGA. Pathology showed weight 159 g (~50th centile), length 20 cm(~50th centile), and OFC 12.5 cm(~10th centile), cranio-facial dysmorphy with a ‘‘V’’-shaped metopic suture, deep-set eyes, shortflattened nose, small and low-set ears, short buccal frenulum, cystic cervical hygroma, as well as postaxial polydactyly of the right hand and left foot with short fingers, micropenis with hypospadias.							{51}
13-N- qt31.3/ 1-1	n.a./ prenatal	AF	de novo	47,+mar[100%]	inv dup(13)(qter→q31.3: :q31.3→qter) array: size 24.2 MB	arrayCGH	see below	{45}
13-N- qt31.3/ 1-1	in week 19 of gestation in sonography: enlarged stomach, postaxial polydactyly, increased nuchal translucency; TOP							{45}
13-N- qt31.3/ 1-2	male/ 15y	PBL	de novo	47,XY,+mar[8]/ 46,XY[12]	inv dup(13)(qter→q31.3: :q31.3→qter) array: 93.37 to qter; besides dup 15q13.3 de novo	different FISH-probes; arrayCGH	Seizures, cleft palate, and learning difficulties	{50} case 12
13-N- qt32/ 1-1	female/ 1d	PBL/ fibroblasts	de novo	47,XX,+mar[98%]/ 46,XX[2%] (sSMC in fibroblasts 8%)	inv dup(13)(qter→q32: :q32→qter)	alpha-, beta-satellite satIII, telomeric , all wcp , YAC-probes (not specified)	see below	{2} case 4 {6} {8} case 13f {11; 12; 16; 25; 44}
13-N- qt32/ 1-1	at birth agenesis of right eye, microphtalmia of left eye, microcephaly, scaphocephaly; bulbous nose, short neck, congenital heart defect; agenesis of corpus callosum, 11 ribs; profound developmental delay, died at 3d due to heart defect;							{2} case 4 {6} {8} case 13f {11; 12; 16; 25; 44}
13-N- qt32/ 1-2	female/ 1w	PBL	de novo	48,XX,+marx2[15%]/ 47,XX,+mar[75%] 46,XX[5%] at birth At 7y 5/75/20	inv dup(13)(qter→q32: :q32→qter)	wcp 13; cep13/21, 14/22, 15, 16, X; probe in 13q32-q33 and subtelomere probe 13q	see below	{7; 12; 16} {8} case 13h {44}
13-N- qt32/ 1-2	at birth right microphtalmia and coloboma, plus tumor of right optic nerve, malformed ears with preauricular ear pit, hemangiomas on forehead, scalp and neck, syndactyly 2./3. toes; At 7y moderate mental retardation, seizures, dysmorphic features, high arched palate, poorly implanted decayed teeth, obese, bulbous nose, bifid tip, epicanthus, early hypotonia, later ataxia and hemiparesis, PDA at birth but normal at 11y;							{7; 12; 16} {8} case 13h {44}
13-N- qt32/ 1-3	male/ 1w	PBL/ fibroblasts	de novo	47,XY,+mar[100%] (sSMC in fibroblasts 100%)	inv dup(13)(qter→q32: :q32→qter)	FISH as specified in {8}	see below	{8} case 13g {12} {14; 16; 44}
13-N- qt32/ 1-3	at birth up to 5y normal weight; at 8y below normal weight; normocephaly, bifid nose anteverted nostrils, hypertelorism, iris and choroid coloboma, seizures, hypotonia, MRI at 10y shows swollen gray matter, hemangiomas of head and back; tapering fingers; died at 10y							{8} case 13g {12} {14; 16; 44}
13-N- qt32/ 1-4	male/ 6m	PBL	de novo	48,XY,+marx2[26%]/ 46,XY[74%] at age of 7y at 6m the two sSMC in 3/25 cells	inv dup(13)(qter→q32: :q32→qter)x2	different FISH probes as specified in {4}	see below	{4} case 3; {12; 16; 25}
13-N- qt32/ 1-4	at birth overlaying occiput which was asymmetrical; low-set ears; eyes widely spaced and cyst in right eye; from 6m on developmental delay; from 21m on seizure disorder; hypertelorism, ptosis of right eyelid, anteverted nares							{4} case 3; {12; 16; 25}
13-N- qt32.3/ 1-1	n.a./ newborn	PBL	de novo	49,+marx3[23%]/ 46[77%]	inv dup(13)(qter→q32.3: :q32.3→qter)x3	array-CGH, subtelomere FISH	Died shortly after birth, very dysmorphic, low set and abnormal ears, preauricular pits	{41}
13-N- qt32.3/ 2-1	female/ postnatal	AF	n.a.	47,XX,del(13)(q32.3), +mar[100]	inv dup(13)(qter→q32.3::q32.3→qter)	M-FISH, CGH	n.a.	{0} case provided by Dr. C. Fuster (Spain)

other neocentromere 13 cases (no sSMC):

reference {4} 1 case {16}

reference {8} 2 cases {16}

reference {17} 1 case

reference {21} 1 case

reference {46} case 3

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
13-N- IMB- qter/ 1-1 to ?-1	see {40}						{40}