What's New:
Cytogenetically visible Copy Number Variations (euchromatic variants)
Transmitted Sub-Telomeric Imbalances
The individual entries below under groups 1,2 and 3 collect imbalances that are usually cytogenetically visible. However:
1. A separate Transmitted Sub-Telomeric Imbalance Collection has been added alongside this Chromosome Anomaly Collection at http://www.ngrl.org.uk/Wessex/subtel_collection.htm.
2. Research and diagnostic applications of array CGH are now revealing just how frequent transmission of submicroscopic imbalances from parents to children is, how often transmission is from a mildly or unaffected parent and how the same imbalances can be found in control cohorts, albeit at reduced frequency. This is reflected in a number of microdeletion and/or microduplication syndromes including for example:
a. The Thrombocytopenia absent radius microdeletion syndrome (TAR) in 1q21.2 in which 75% of parents have the same deletion and are unaffected (Klopocki E et al, Am J Hum Genet 2007;80:232-40).
b. The 1q21.2 microdeletion/duplication syndrome in which the probands have a wide variation of phenotypes and some parents with the same imbalancea are unaffected (Mefford HC et al, N Engl J Med 2008;359:1685-99).
c. The 15q13.3 microdeletion/microduplication syndrome which also displays a wide range of expressivity (Sharp AJ et al, Nat Genet 2008;40:322-8).
d. The 16p13.11 microdeletion/microduplication in which the occurrence of the same duplication (but not the deletion) in controls casts doubt on the causality of the duplication but not the deletion (Hannes FD et al, J Med Genet 2009;46:223-32).
e. The 22q11.2 microduplication syndrome in which unaffected parents are not uncommon (Yobb TM et al, Am J Hum Genet. 2005;76:865-76).
Group 1
1. dup(1)(q31.1q31.2): a Group 1 duplication of 13.9 Mb in the medial long arm of chromosome 1 was ascertained in the male half of a couple referred for two miscarriages (Mrasek et al, Cytogenet Genome Res 2008;121:286-287. Both he and his mother carried the same duplication and were phenotypically normal. The fetal losses were not karyotyped but the mother and her liveborn son were chromosomally normal. BAC array analysis showed that the duplication extended from megabase pairs 184.95 to 197.91 and contained 56 known genes of which 25 had OMIM entries.
2. del(4)(q34.1q34.3): a Group 1 deletion of 9.4 Mb from the distal long arm of chromosome 4 was ascertained in 30 year old female referred for a history of miscarriages and reported in abstract (Bateman et al, J Med Genet 2007;44:Suppl1 3.28). The deletion included a number of genes in bands 4q34.1 and 4q34.2 as well as a gene desert in 4q34.3. The phenotype of the patient was normal but parental samples were not available at the time and formal proof of transmission was not obtainable.
3. dup(4)(p16.1p16.1): a Group 1 interstitial duplication of 3.3 Mb between ~ 8.5 and 11.5 megabase pairs in the distal short arm of chromosome 4 was ascertained in the phenotypically normal father of a pregnancy in which additional material at the end of the short arm of chromosome 4 had been detected in amniotic fluid cultures (add(4)(p16)) (Rodriguez et al, Am J Med Genet Part A 2007;143A:995-998). The father had transmitted this duplication to his older phenotypically normal daughter. The couple chose to terminate the add(4)(p16) pregnancy and the exact nature of the add(4) could not be determined. However, the authors discuss the possibility that the dup(4) predisposes to larger rearrangements of 4p that might explain the add(4) and the fetal dwarfism found in two other pregnancies that the couple had chosen to terminate.
4. del(6)(q22.31q23.1): a Group 1 deletion of at least 9.9 Mb from the medial long arm of chromosome 6 was ascertained in a 34 year old woman referred after two miscarriages (Hansson et al, Am J Med Genet Part A 2007;143A:1354-1357). She was phenotypically normal but her parents were not available for testing. BAC array analysis showed that the deletion contains at least 28 genes, of which 10 had OMIM entries. Her affected son had not inherited her deletion.
5. dup(7)(p22.3pter) from an unbalanced der(3)t(3;7)(psubtel;p22.3) translocation: a Group 1 duplication of the terminal 3.9 Mb of the short arm of chromosome 7 was reported in abstract (Willatt et al, J Med Genet 2008;45:3.23); Affymetrix 250k SNP array analysis showed that the duplication contained at least 53 genes of which 21 had OMIM entries. FISH showed that the duplication was attached to the intact tip of the short arm of chromosome 3. This imbalance must overlap the 7p22-pter deletion previously described in brief in an affected child and normal parent (Mascarello et al, Am J Med Genet 1991;38:37-42).
6. del(11)(q14.3q22.1): a Group 1 deletion of at least 8.5 Mb between megabase pairs 91.37 to 99.93 from the medial long arm of chromosome 11 was found at prenatal diagnosis after a positive Down syndrome maternal serum screening result (Goumy et al, Am J Med Genet Part A 2008;146A:2668-2672). The same deletion was found in the mother, who had endometrial polyps, toe campodactyly, hypermetropia, astigmatism and strabismus, and the maternal grandfather who was phenotypically normal. The deletion contained 22 coding genes and includes the haplosufficient 3.6 Mb deletion previously described by Li et al (Cytogenet Genome Res 2002;97:158-162). The daughter was normal at term and the authors proposed that the normal phenotype could be due to functional complementation as the majority of the genes involved had related isoforms elsewhere in the genome.
7. dup(12)(q21.31q22): this Group 1 duplication of 12q with a minimum size of 6.2 Mb was ascertained at prenatal diagnosis for maternal age and has now been published (Barber et al, Am J Med Genet Part A 2007;143A: 615-618). The duplication contained 25 known and 23 novel genes. The same duplication was present in the unaffected mother. The daughter was normal at term and developing normally at just under 3 years of age.
8. del(13)(q21.1-q21.31): a Group 1 deletion of 10.7 Mb from medial 13q between base pairs 53,513,760 and 64,180,663 was found in a woman of 32 referred for recurrent miscarriages (Roos et al, Am J Med Genet Part A 2008;146A:2417-2420). The deletion contained 15 coding transcripts. Transmission from a parent could not be established as parental samples were not available.
9. del(13)(q21.1-q21.33): a Group 1 deletion of 14.5 Mb from medial 13q between base pairs 53,624,500 and 68,063,900 was ascertained at prenatal diagnosis for polyhydramnios (Filges et al, Am J Med Genet Part A 2009;149A:237-241). The same deletion was found in the phenotypically normal mother and maternal grandfather who had both undergone professional education. The grandmaternal pregnancy had not been marked by polyhydramnios. At the age of 5 the index patient had no dysmorphic features and normal motor and cognitive development. The authors could not exclude the possibility that the deletion was the cause of his 9 month delay in fine motor skills and expressive language but his pigmentary anomalies remained unexplained in view of their absence in his relatives and other 13q deletions.
Group 2
1. del(2)(q13q13): a Group 2 deletion of 1.62 Mb from the proximal long arm of chromosome 2 between base pairs 111,155,700 to 112,776,503 was ascertained in a boy with birth asphyxia and failure to thrive at 6 months of age (Family 3 in Bisgaard et al, Eur J Med Genet 2007;50:243-55). Psychomotor retardation, hypotonia, epilepsy and mild dysmorphic features were later recorded. The deletion was found in his unaffected mother and mildly affected brother who had also had birth asphyxia. The authors noted overlapping copy number variations of up to 1.8 Mb in size and concluded that the deletion is probably coincidental.
2. del(2)(q14.1q14.2): a Group 2 deletion of 2q14.1-q14.2 was found in an affected boy, from a consanguineous family, and his phenotypically normal father and brother (Barber et al, Eur J Hum Genet 2006;14:739-743). The deletion included the homeobox engrailed 1 gene (EN1) and nineteen other genes. BAC FISH also showed that this deletion overlapped with a previously reported transmitted deletion of 2q13-q14.1 that had no phenotypic consequences and is already in this collection (Sumption and Barber, J Med Genet 2001;38:125-126). The combined deleted regions contained a total of 32 genes and comprise the final 5.25 Mb of the ancestral chromosome 2B from which chromosome 2 was formed in man.
3. del(3)(p11.2p12.3): a Group 2 deletion of ~10 Mb from the proximal short arm of chromosome 3 was reported in abstract (Willatt et al, J Med Genet 2008;45:3.23). Affymetrix 250k SNP array analysis identified this deletion in an affected child and phenotypically normal father.
4. dup(4)(q35.1-q35.2) (see also del(18)(q21.1q21.1): a Group 2 duplication of 2.71 Mb from distal 4q between base pairs 185,922,600 and 188,630,411 was ascertained in a girl with pulmonary atresia at birth (Family 6 in Bisgaard et al, Eur J Med Genet 2007;50:243-55). She had dysmorphic features, short stature, frequent ear infections and psychomotor delay - partly attributed to her cyanotic heart disease and frequent admission for infections. The duplication was found in the father and paternal grandfather, neither of whom had heart disease, although the father had hypermetropia and small hands. The duplication was regarded as coincidental to the deletion of 18q21.1 and the phenotype of the index patient due to the reports of other Group 2 sub-telomeric 4q duplications (see http://www.ngrl.org.uk/Wessex/subtel_collection.htm).
5. del(8)(p23.1p23.2): a Group 2 deletion of 4.61 Mb from the distal short arm of chromosome 8 was ascertained in a woman of 22 with moderate learning difficulties, pulmonary stenosis and sensorineural deafness and reported in abstract (Case 4 in Barber et al, J Med Genet 2008;45:Suppl1 3.06). The same deletion was found in her phenotypically normal mother and brother.
6. del(10)q11.21q11.23): a Group 2 deletion of 6.18 Mb from the proximal long arm of chromosome 10 between base pairs 45,432,617 and 51,611,575 was found in girl with birth asphyxia, severe psychomotor retardation, dysmorphic features, frequent infections and atrophy of the brain (Family 4 in Bisgaard et al, Eur J Med Genet 2007;50:243-55). The same deletion was found in her unaffected mother and two of her three elder sisters. The deletion was though to be coincidental as the phenotype of the index patient was consistent with Bohring Opitz syndrome but the unmasking of a recessive allele within the deleted segment could not be excluded.
7. dup(13)(q21.1-q21.32): a Group 2 duplication of 11.2 Mb from medial 13q between base pairs 57,629,383 and 68,180,810 was ascertained in a boy of 4 with no dysmorphic features but delay in speech, language and fine motor skills consistent with autistic spectrum disorder (Daniel et al, Am J Med Genet Part A 2007;143A:2452-2459). The same deletion was found in his phenotypically normal mother and maternal grandfather. The duplicated segment contained just 6 coding genes and the authors showed how transmitted anomalies were, in general, characterized by low gene density and a relatively high copy number variant content.
8. del(18)(q21.1q21.1) (see also dup(4)(q35.1-qter): a Group 2 deletion of 2.09 Mb from medial 18q between base pairs 42,654,883 and 44,739,800 was ascertained in a girl with pulmonary atresia at birth (Family 6 in Bisgaard et al, Eur J Med Genet 2007;50:243-55). She had dysmorphic features, short stature, frequent ear infections and psychomotor delay partly attributed to her cyanotic heart disease and frequent admission for infections. The deletion was found in the father and paternal grandfather, neither of whom had heart disease, although the father had hypermetropia and small hands. The deletion was regarded as causal of the heart disease in the index patient because of the association between heart disease and deletions of 18q.
9. dup(18)(q21.31q22.2): a transmitted Group 2 duplication of ~12 Mb from 18q21.31 to 18q22.2 was reported by in three adult siblings with a degree of cognitive delay and mild dysmorphism (Ceccarini et al, Am J Med Genet 2007;143A:343-348). By contrast, the mother had a University degree and a normal phenotype explained by her mosaicism for the same duplication.
Group 3:
1. del(1)(p34.1p34.2): a Group 3 duplication of 3.44 Mb from distal 1p between base pairs 40,749,241 and 44,190,769 was ascertained in a boy with failure to thrive, hypotonia, delayed psychomotor development, brain hypoplasia and diabetes mellitus (Family 2 in Bisgaard et al, Eur J Med Genet 2007;50:243-55). The deletion was in his milder but similarly affected father and thought to be causal because of the phenotypic overlap with other reported cases.
2. del(1)(p31.3p32.1): a Group 3 deletion of 5.54 Mb from medial 1p between base pairs 59,028,905 and 64,570,597 was ascertained in a girl of eight months with trigonocephaly. MRI was normal but urinary tract infections, seizures, psychomotor delay, behavioural problems, hearing impairment, hypermetropia and dysmorphic features were later recorded (Family 1 in Bisgaard et al, Eur J Med Genet 2007;50:243-55). The deletion was found in her mildly affected mother and the maternal grandfather who had psychological disturbances. The authors concluded that the phenotype of the proband was too severe to be explained by the deletion alone, but could not exclude the possibility that deletion might be the cause of the psychological disturbances.
3. del(3)(p25.3pter): a second mildy affected mother daughter diad with this deletion has been reported (Takagishi et al, Am J Med Genet Part A 2006;140A:1587-1593). This Group 3 deletion was ascertained at preconceptional counseling of a 34 year old whose sister had an independent chromosomal imbalance. Array CGH showed that the deletion included the terminal 8.8 -10 Mb of 3p. The consultand had minor dysmorphisms and moderate scoliosis. Her subsequent daughter was also mildy affected with no developmental delay of milestones at the age of 15 months. The authors contrast their family with the established 3p deletion syndrome and discuss ascertainment bias or chromosomal non-penetrance as possible explanations. Their position is supported by the unbalanced 3;8 translocation reported by Shrimpton et al (Am J Med Genet 2006;140A:388-391) with a deletion of at least 6.9 Mb of 3p and a "virtually normal phenotype". A third 3p25 deletion diad has been reported in abstract (Sklower-Brooks et al, Am J Hum Genet 2002;71:301(754A)).
4. del(4)(p15.33-p16.3): a Group 3 deletion of 7.89 Mb from distal 4p between base pairs ~ 3,600,000 and 11,490,000 4,739,800 was in a boy of 15 months with psychomotor developmental delay, speech delay and dysmorphic features (Basinko et al, Am J Med Genet Part A 2008;146A:899-903). The same deletion was found in his mildly affected mother who had learning difficulties at school and was late walking. The authors noted that the deletion is located between the Wolf-Hirschhorn Syndrome (WHS) critical region(s) in distal 4p16.3 and the proximal 4p critical region in 4p15.2 to 4p15.32. Neither the son nor mother was regarded as having WHS.
5. del(4)(q34qter): a Group 3 ~ 7.5 Mb terminal deletion of 4q was ascertained in a girl with primary amenorrhoea and aplasia of the uterus and vagina (Bendavid et al, Eur J Med Genet 2007;50:66-72). Her mother had the same deletion and features consistent with a distal 4q deletion but for Fallopian cancer. The authors discuss the possibility that a gene for Mayer-Rokitansky-Kuster-Hauser syndrome maps to the deleted region despite the evident fertility of the mother.
6. dup(6)(q21q22.1): a Group 3 duplication of 5-10 Mb in medial 6q was ascertained in a boy with IUGR, moderate mental retardation and facial dysmorphism (Pazooki et al, Eur J Med Genet, 2007;50:60-5). The same duplication was found in his mother who had a similar phenotype but milder dysmorphism.
7. dup(7)(p11.2p12): a Group 3 duplication of 7p11.2 to 7p12 was ascertained in a boy, mother and grandmother who all had mild cognitive deficiencies (Leach et al, Am J Med Genet Part A 2007;143A:1489-93). The duplication did not include the candidate Silver Russell Silver syndrome candidate gene GRB10 and the mild phenotype consistent with overlapping duplications from the literature.
8. dup(8)(p23.1p23.2): a Group 3 insertional duplication of 6.8 Mb from distal 8p was found in a boy with speech delay and ICD-10 autism and his mother with who had epilepsy and learning problems (Glancy et al, Eur J Hum Genet 2009;17:37-43). The duplication included 41 known and 22 novel genes but only the microcephalin gene (MCPH1) was regarded as a plausible autism candidate gene.
9. del(10)(q22.3q23.31): a Group 3 deletion of 7.6 Mb from medial 10q between megabase pairs 81.624 and 89.211 was ascertained in a boy diagnosed with autism at the age of 3 years and 6 months (Family 1 in Balciuniene et al, Am J Med Genet 2007;80:938-947). The same deletion was found in his mother, maternal grandfather, sister and seven other family members. The deletion contained 32 known coding genes but was distal to the PTEN gene. The deletion co-segregated with a wide range of cognitive and behavioural phenotypes from academic difficulties to ADHD and autism. The phenotype appeared more pronounced in males than females.
10. dup(11)(p14.3p15.1): a Group 3 duplication of the distal short arm of chromosome 11 was ascertained in a boy of 2 with mental retardation, speech delay, severe behavioural problems and dsymorphism (Wyandt et al, Exp Mol Pathol 2006;80:262-6). The same duplication was found in his mother who had mild mental retardation, behavioural problems when at school and similar facial features to her son.
11. del(11)(q14.3q22.3): a Group 3 deletion of 17.3 Mb from medial 11q between base pairs 89,492,818 and 106,832,040 was ascertained at prenatal diagnosis for multiple ultrasound anomalies (Sparkes et al, Prenat Diagn 2009;29:283-6). Severe left talipes equinovarus, minor cardiac abnomalities and global cerebellar hypolplasia were found after the pregnancy was terminated. The same deletion was found in the mother who had surgically corrected talipes and cerebellar atrophy. The deletion contained 68 genes and a proximal 900 kb flanking duplication containing 4 genes and interrupting a fifth. The mother had normal or near-normal intelligence, neurological status, general health and fertility.
12. dup(12)(p12.3p11.2) (associated with a p11.2 to q14.1 pericentric inversion): a Group 3 family with an 11 Mb duplication of proximal 12q between base pairs 17,695,757 and 28,878,898 was ascertained in a 9 year old boy with mental retardation and a characteristic face (Liang et al, Am J Med Genet 2006;140A:238-244). The same rearrangement was found in the father and mapped using the Affymetrix GeneChip. Similar phenotypic features were found in the father and son including intellectual disability or developmental delay, EEG suggesting neuronal dysfunction of the cerebral cortex and a degree of dysmorphism.
13. del(13)(q31.1q31.1): a Group 3 deletion of 2.86 Mb from distal 13q between base pairs 80,506,070 and 83,363,448 was ascertained in a boy with severe developmental delay and hypotonia, unresponsiveness, eating problems, microcephaly, dysmoprphism, neck webbing and large fontanels (Family 5 in Bisgaard et al, Eur J Med Genet 2007;50:243-55). The deletion co-segregated with learning disabilities in the father, paternal grandmother, paternal great grandmother and three other family members. The deletion contained only three genes and the authors thought it more likely that the deletion was co-incidental to the both the severe phenotype of the index patient as well as the learning disabilities in the six other family members.
14. dup(13)(q21.1q21.33): a Group 3 duplication of 11.95 Mb in medial 13q between base pairs 57,108,113 and 69,059,793 was ascertained via a boy of 8 with language delay and triplication of the same segment (Lopez-Exposito et al, Am J Med Genet Part A 2008;146A:1190-1194). The direct duplication was found in his father, paternal grandfather and two brothers. The phenotype of the duplication carriers was thought to extend into the normal range but macrocephaly, some facial dysmorphism, a tendency to late tooth eruption and adult-onset sensorineural hearing loss were common features. In addition, the triplication carrier had borderline mental development and language delay. The triplication derived from a paternal duplication is a very unusual finding and a warning that tandem duplications may not always be transmitted intact.
15. dup(13)(q21.31q31.1): a Group 3 family with a large 21 Mb duplication of medial 13q between 61.3 and 82.2 Mb pairs was ascertained in a boy with neonatal feeding problems and delayed developmental milestones (Mathijssen et al, Am J Med Genet 2005;136A:76-80). The duplication was found in 5 other family members over three generations and mapped with array CGH. The authors considered that the relatively mild phenotype for the size of the duplication was due to the gene poor nature of the duplicated region which contained 40 genes.
16. del(18)(p11.2pter): another Group 3 transmitted deletion of most of the short arm of chromosome 18 was ascertained in a girl of 4 with developmental delay (Maranda et al, BMC Med Genet 2006;7:60). The same deletion was found in her mother and sister. The degree of cognitive impairment was variable within the family.
Copy Number Variations (euchromatic variants):
1. amp(4)(p16.1p16.1): a cytogenetically visible amplification of 4p16.1 co-segregated with microtia in a large family reported by Balikova et al (Am J Hum Genet 2008;82:181-7). Five tandem copies of a 750 kb amplicon were present on the amplified chromosome and associated with a variable ophthalmological phenotype in 10 members of a three generation pedigree. The amplicon contained olfactory receptor, defensin and BUB gene family members, which are known to be copy number variable. The dopamine receptor D5 gene (DRD5) was the only unique gene within the amplicon but was thought an unlikely candidate for the ophthalmological features. It seems most likely that this amplification is a co-segregating euchromatic variant by analogy with the 8p23.1 olfactory receptor/defensin copy number variations. However, the authors propose a other mechanisms whereby this amplification might be causal.
2. var(15)(q11.2q11.2): a further cytogenetically visible copy number variation of proximal 15q was ascertained in a boy of 10 months with hypotonia, developmental delay and a hypsarrhythmic EEG consistent with West syndrome (Carelle-Calmels et al, Eur J Med Genet 2008;51:547-557). A genuine interstitial BP2-BP3 duplication of the Prader-Willi/Angelman critical region was found adjacent to the CNV on the same chromosome. The duplication was of maternal origin but only the CNV was found in the mother, maternal grandmother and two other family members. Amplification of the NF1/GABRA5 pseudogenes was found using FISH with BAC RP11-275E15 as well as RP11 library BACs 2F9, 388D24 and 566K19.The phenotype of the index patient was unusually severe for a BP2-BP3 duplication but the phenotype of the family members with the more proximal CNV was normal.
3. var(9)del(9)(q13q12.12): Willatt et al report a novel deletion variant of the proximal long arm of chromosome 9 in a total of 8 individuals (3 families and 2 individuals) (Eur J Hum Genet, 2006, Sep 20; [Epub ahead of print] PMID: 16985501). The variety of reasons for which these patients were ascertained, and the phenotypically normal parents, indicates that this is another euchromatic variant with no phenotypic effect. BACs from the deleted region mapped to both the long and short arms of chromosome 9 indicating a reduction of copy number from 4 to 3 in the variant chromosomes. These variants are likely to be the same as the deletion variants reported in Abstract by Winters et al (Am J Hum Genet 1998;63:Suppl, A41) and the corresponding duplication variants reported by Winters et al (op cit) and, again in abstract, by Mevatee et al (Chromosome Res 2005;13:Suppl1,1.33-P).
3b var(9)dup(9)(q13q21.12): and var(9)trp(9)(q13q21.12); Willatt et al (op cit) found that the same region was involved with the classical euchromatic variants in which one or more extra G-dark euchromatic bands are found within the major 9qh heterochromatic block.
3c. var(9)dup(9)(p11.2p13.1): Willatt et al (op cit) also confirmed that the same region is involved in classical short arm variants in which extra G-dark bands are found in the short arm of chromosome 9.
3d. var(9): the results of 1a,b,and c help to define pericentromeric regions of chromosome 9 that are largely segmentally duplicated. These extend over 8 Mb of the short arm as far as 9p13.1 and over 4 Mb of the long arm region as far as 9q12.12. Multiple smaller copy number variations have been found within these regions in normal individuals. There is no established connection between any phenotypic anomalies and copy number changes of this 12 Mb region.
4. var(9)(p12p12): Lecce et al (Hum Genet 2006;118:760-766) found an alternative basis for the euchromatic variants of 9p12 in the form of multiple copies of a 1 Mb section of segmentally duplicated euchromatin from 9p12 that co-hybridises to proximal 9q. In two Group 1 families ascertained at prenatal diagnosis, amplification of 9p12 BACs RP11-402N8, 38P6 and 15E1 was found in the prenatal material, the phenotypically normal fathers and in other family members. In a third case ascertained with Premature Ovarian Failure (POF), POF was explained by a pre-mutation in the FMR-1 gene and amplification of 9p12 with the same probes regarded as an incidental finding. Copy number in 100 normal controls varied from 1 to 3 and copy number in the three euchromatic variant families was estimated at 7, 8 and 12.
5. var(16)(p11.2p11.2): Lopez Pajares et al (Prenat Diagn 2006;26:535-538) tell a cautionary tale of parents opting to terminate a pregnancy with a euchromatic variant 16 interpreted as a clinically significant abnormality by another laboratory. The authors showed that BAC RP11-261A7 within 16p11.2 was amplified consistent with euchromatic variation in both the mother and grandfather.
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National Genetics Reference Laboratory
(Wessex)
Salisbury District Hospital
Salisbury