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
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Figure Legends
Figure 1:
- The proband’s second daughter, born with multiple malformations.
- The proband’s sister with Cornelia de Lange syndrome.
- 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)