Discussion:
The discovery of the chromosome translocation was an important event for this family, given the role this new diagnosis had in their lives. The proband’s mother stated that she immediately recognized the similarities between her daughter with Cornelia de Lange syndrome and her now deceased granddaughter. She describes having a strong suspicion that her daughter and granddaughter were affected by the same condition, and she felt a profound sense of closure after learning of the chromosome abnormality and its role in both her daughter and deceased granddaughter. She suspected that her deceased twin sons were affected with the chromosome abnormality as well.
Chromosome aberrations that result from abnormal segregation of parental balanced chromosome rearrangements are a well-known cause of abnormal development. However, a standard karyotype performed on the proband’s sister in the late 1980’s failed to detect the chromosome imbalance because of the “cryptic” sub-telomeric location of the breakpoints. Literature search did not identify other cases with a similar balanced translocation or a similar combination of distal 1q deletion/6q duplication, and thus, there is no clear basis for prediction of likely phenotypic features. However, the phenotypic spectrum associated with distal deletion of chromosome 1q is known to include cognitive impairment, growth retardation, microcephaly, agenesis of the corpus callosum and distinctive facial features (van Bon, Koolen et al. 2008). Thus, the features present in II.1 (the proband’s sister) are consistent with 1q deletion. In addition, some of the features of III.1, such as hypoplastic corpus callosum are consistent with 1q deletion. The phenotypic effect of the distal 6q duplication is difficult to evaluate, since we were not able to identify any reports with a similar duplication. It seems likely that a duplication of this size, containing 39 genes, contributed to the clinical picture.
The proband’s sister received the diagnosis of Cornelia de Lange syndrome prior to any knowledge of the molecular genetic basis for this condition. Now we know that most cases of de Lange syndrome are due to point mutations in NIPBL (Musio et al., 2006); however, there are several reports describing de Lange syndrome in children with various segmental aneuploidies (DeScipio, Kaur et al. 2005). We note one such case which had a distal 1q deletion that is similar to the one we report (Borck, Redon et al. 2004). Thus, the diagnosis of de Lange syndrome in the proband’s sister was not necessarily incorrect. However, the reassurance given to the family that the condition was unlikely to recur turns out to have been incorrect. As the proband’s children reach reproductive age, they will be duly informed about the possibility of being carriers of a chromosome translocation.
Interestingly, the outcomes of the two individuals with 1q deletion/6q duplication were quite different, with one living into adulthood and the other dying in the neonatal period. This observation raised the concern that the proband’s daughter may have had a second diagnosis, explaining the lethal metabolic acidosis. To address this possibility, we questioned whether any genes in the 1q deletion region or the 6q duplication region might plausibly have contributed to the acidosis. Specifically, we re-reviewed the exome data to identify whether the proband’s father harbored any deleterious variants in any of the genes in the 1q deletion region; however, none were identified. The chromosome 6q duplication region was noted to contain the gene BRP44L, in which homozygous loss of function results in pyruvate carrier deficiency (OMIM 614741), a known cause of metabolic acidosis. However, it is difficult to understand how the presence of three copies of this locus might lead to complete loss of function. Also, as noted above, biochemical studies on cultured fibroblasts did not identify any evidence of abnormal pyruvate metabolism. At this point, we do not have an adequate explanation for the profound metabolic acidosis.
It is tempting to speculate that the twin children (II 1 and II 2 in Figure 3) may also have been affected by a chromosome imbalance due to the parental translocation. However, given their severe prematurity, non-specific phenotypic features and demise many years ago, the answer to this question is likely to remain a mystery.
This case illustrates the value of revisiting old diagnoses using new technology, especially when recurrence is a possibility.
References
Borck, G., R. Redon, D. Sanlaville, M. Rio, M. Prieur, S. Lyonnet, M. Vekemans, N. P. Carter, A. Munnich, L. Colleaux and V. Cormier-Daire (2004). ”NIPBL mutations and genetic heterogeneity in Cornelia de Lange syndrome.” J Med Genet 41 (12): e128.
DeScipio, C., M. Kaur, D. Yaeger, J. W. Innis, N. B. Spinner, L. G. Jackson and I. D. Krantz (2005). ”Chromosome rearrangements in cornelia de Lange syndrome (CdLS): report of a der(3)t(3;12)(p25.3;p13.3) in two half sibs with features of CdLS and review of reported CdLS cases with chromosome rearrangements.” Am J Med Genet A 137a (3): 276-282.
Musio, A., Selicorni, A., Focarelli, M. L., Gervasini, C., Milani, D., Russo, S., Vezzoni, P., Larizza, L. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nature Genet. 38: 528-530, 2006.
van Bon, B. W., D. A. Koolen, R. Borgatti, A. Magee, S. Garcia-Minaur, L. Rooms, W. Reardon, M. Zollino, M. C. Bonaglia, M. De Gregori, F. Novara, R. Grasso, R. Ciccone, H. A. van Duyvenvoorde, A. M. Aalbers, R. Guerrini, E. Fazzi, W. M. Nillesen, S. McCullough, S. G. Kant, C. L. Marcelis, R. Pfundt, N. de Leeuw, D. Smeets, E. A. Sistermans, J. M. Wit, B. C. Hamel, H. G. Brunner, F. Kooy, O. Zuffardi and B. B. de Vries (2008). ”Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis.” J Med Genet 45 (6): 346-354.
Figure Legends
Figure 1:
  1. The proband’s second daughter, born with multiple malformations.
  2. The proband’s sister with Cornelia de Lange syndrome.
  3. The proband’s brother, with severe developmental delay but no specific diagnosis.
Figure 2:
Ideogram of chromosomes 1 and 6, with arrows indicating the position of breakpoints in the subtelomeric region of both chromosomes. Partial karyotype of proband with arrows indicating the position of breakpoints.
Metaphase FISH studies of the proband, showing that the 1q subtelomeric probe identifies the 6q telomeric region and the 6q subtelomeric probe identifies the 1q subtelomeric region, indicating a translocation between 1q and 6q.
Figure 3:
Pedigree of the family showing the proband (II 5), her mother (I 1), her affected sister (II 6) and her deceased daughter (III 2)