What's New: Transmitted imbalances and Euchromatic variants (below)
What’s new
Group 1:
1. dup(12)(q21.31q22): a new Group 1 duplication of 12q with a minimum size of 6.2 Mb was ascertained at prenatal diagnosis for maternal age (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.
Group 2:
1. dup(1)(q11q22): a Group 2 family with a transmitted duplication of 1q11 to 1q22 was ascertained in an otherwise phenotypically normal boy of 9 with T cell lymphoblastic leukaemia and his mother (Chan et al, 2002). This family is already included in the Chromosome Anomaly Collection but, since then, two further relevant publications have appeared:
a. Sawyer et al (Am J Med Genet 2007;143A:338-342) published a third de novo case of a duplication of this region associated with common findings of micrognathia, low set ears and a short neck. The contrast between the three de novo cases and the single Group 2 family is consistent with the idea of chromosomal non-penetrance (see del(3p)(p25.3-pter) below).
b. Klopocki et al (Am J Hum Genet 2007;80:232-240) identified a 200 kb deletion within 1q21.1 in multiple patients with Thrombocytopenia Absent Radius (TAR) syndrome. However, in 75% of cases, the same deletion was present in a normal parent. The authors propose a modifying locus to explain the discrepancy between parents and children. This deletion must lie inside the duplicated region and it is remarkable that a distinct discrepancy, in a phenotype involving T lymphocytes, is found in families with both visible and sub-microscopic deletions and duplications of this region.2. dup(18)(q21.31q22.2): a new transmitted Group 2 duplication of 18q21.31 to 18q22.2 was was reported by Ceccarini et al (Am J Med Genet 2007;143A:343-348) in a mother and three adult siblings. All three had a degree of cognitive delay and mild dysmorphism. By cntrast the mother had a University degree and a normal phenotype explained by her mosicism for the same duplication.
3. 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.
Group 3:
1. del(4)(q34-qter): a further Group 3 family with a transmitted deletion of 4q34-4qter in a mother and daughter with a variable phenotype was reported by Bendavid et al (Eur J Med Genet 2007;50:66-72). At age 54, the mother had a rare gynaecological cancer thought to be related to deletion of the FAT gene which maps to the deleted region. The daughter had the same deletion and isolated aplasia opf the uterus and vagina consistent with the autosomal recessive Mayer-Rokitansky-Kuster-Hauser syndrome (OMIM #277000).
2. del(3)(p25.3-pter): a second mildy affected mother daughter diad with this deletion has been reported by 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 by Sklower-Brooks et al (Am J Hum Genet 2002;71:301(754A).
3. 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 by Bendavid et al (Eur J Med Genet 2006 doi:10.1016/j.ejmg.2006.09.003). 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.
4. dup(12)(p12.3p11.2): a Group 3 family with an 11 Mb duplication (associated with a p11.2 to q14.1 pericentric inversion) was ascertained in a 9 year old boy with mental retardation and a characteristic face by 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.
5. dup(13)(q21.31q31.1): a Group 3 family with a large 21 Mb duplication of 13q was ascertained in a boy with neonatal feeding problems and delayed developmental milestones by 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 only 40 genes.
6. 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 Medical Genetics 2006;7:60 oi:10.1186/1471-2350-7-60). The same deletion was found in her mother and sister. The degree of cognitive impairment was variable within the family.
1a. 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, 2007;15:45-55). 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).
1b. 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.
1c. 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.
1d. 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.
2. 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.
3. 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