6 research outputs found
Cryptic genomic imbalances in patients with de novo or familial apparently balanced translocations and abnormal phenotype
<p>Abstract</p> <p>Background</p> <p>Carriers of apparently balanced translocations are usually phenotypically normal; however in about 6% of <it>de novo </it>cases, an abnormal phenotype is present. In the current study we investigated 12 patients, six <it>de novo </it>and six familial, with apparently balanced translocations and mental retardation and/or congenital malformations by applying 1 Mb resolution array-CGH. In all <it>de novo </it>cases, only the patient was a carrier of the translocation and had abnormal phenotype. In five out of the six familial cases, the phenotype of the patient was abnormal, although the karyotype appeared identical to other phenotypically normal carriers of the family. In the sixth familial case, all carriers of the translocations had an abnormal phenotype.</p> <p>Results</p> <p>Chromosomal and FISH analyses suggested that the rearrangements were "truly balanced" in all patients. However, array-CGH, revealed cryptic imbalances in three cases (3/12, 25%), two <it>de novo </it>(2/12, 33.3%) and one familial (1/12, 16.6%). The nature and type of abnormalities differed among the cases. In the first case, what was identified as a <it>de novo </it>t(9;15)(q31;q26.1), a complex rearrangement was revealed involving a ~6.1 Mb duplication on the long arm of chromosome 9, an ~10 Mb deletion and an inversion both on the long arm of chromosome 15. These imbalances were located near the translocation breakpoints. In the second case of a <it>de novo </it>t(4;9)(q25;q21.2), an ~6.6 Mb deletion was identified on the short arm of chromosome 7 which is unrelated to the translocation. In the third case, of a familial, t(4;7)(q13.3;p15.3), two deletions of ~4.3 Mb and ~2.3 Mb were found, each at one of the two translocation breakpoints. In the remaining cases the translocations appeared balanced at 1 Mb resolution.</p> <p>Conclusion</p> <p>This study investigated both <it>de novo </it>and familial apparently balanced translocations unlike other relatively large studies which are mainly focused on <it>de novo </it>cases. This study provides additional evidence that cryptic genomic imbalances are common in patients with abnormal phenotype and "apparently balanced" translocations not only in <it>de novo </it>but can also occur in familial cases. The use of microarrays with higher resolution such as oligo-arrays may reveal that the frequency of cryptic genomic imbalances among these patients is higher.</p
Prenatal diagnosis of a cervical teratoma with a cytogenetic study
We describe a cervical teratoma revealed in the prenatal period that was
studied cytogenetically. We were recently confronted with the case of a
fetal solid neck mass suggestive of a teratoma. After termination of
pregnancy the tumor was studied cytogenetically. This is the first case
in the recent literature where a clone of cells with an additional
chromosome marker has been detected. Cytogenetic study of the fetal
blood in addition to cytogenetic study of the tumor after the
termination of pregnancy showed the karyotypes 46,XY and 46,XY/47,XY +
m, respectively. Fetal cervical teratoma is a rare condition. Genetic
investigation in the case should be considered in order to reveal
chromosome rearrangements
Exploring the Genetic Causality of Discordant Phenotypes in Familial Apparently Balanced Translocation Cases Using Whole Exome Sequencing
Familial apparently balanced translocations (ABTs) are usually not associated with a phenotype; however, rarely, ABTs segregate with discordant phenotypes in family members carrying identical rearrangements. The current study was a follow-up investigation of four familial ABTs, where whole exome sequencing (WES) was implemented as a diagnostic tool to identify the underlying genetic aetiology of the patients’ phenotypes. Data were analysed using an in-house bioinformatics pipeline alongside VarSome Clinical. WES findings were validated with Sanger sequencing, while the impact of splicing and missense variants was assessed by reverse-transcription PCR and in silico tools, respectively. Novel candidate variants were identified in three families. In family 1, it was shown that the de novo pathogenic STXBP1 variant (NM_003165.6:c.1110+2T>G) affected splicing and segregated with the patient’s phenotype. In family 2, a likely pathogenic TUBA1A variant (NM_006009.4:c.875C>T, NP_006000.2:p.(Thr292Ile)) could explain the patient’s symptoms. In family 3, an SCN1A variant of uncertain significance (NM_006920.6:c.5060A>G, NP_008851.3:p.(Glu1687Gly)) required additional evidence to sufficiently support causality. This first report of WES application in familial ABT carriers with discordant phenotypes supported our previous findings describing such rearrangements as coincidental. Thus, WES can be recommended as a complementary test to find the monogenic cause of aberrant phenotypes in familial ABT carriers
Cryptic genomic imbalances in patients with de novo or familial apparently balanced translocations and abnormal phenotype
Background: Carriers of apparently balanced translocations are usually
phenotypically normal; however in about 6% of de novo cases, an
abnormal phenotype is present. In the current study we investigated 12
patients, six de novo and six familial, with apparently balanced
translocations and mental retardation and/or congenital malformations by
applying 1 Mb resolution array-CGH. In all de novo cases, only the
patient was a carrier of the translocation and had abnormal phenotype.
In five out of the six familial cases, the phenotype of the patient was
abnormal, although the karyotype appeared identical to other
phenotypically normal carriers of the family. In the sixth familial
case, all carriers of the translocations had an abnormal phenotype.
Results: Chromosomal and FISH analyses suggested that the rearrangements
were “truly balanced” in all patients. However, array-CGH, revealed
cryptic imbalances in three cases (3/12, 25%), two de novo (2/12,
33.3%) and one familial (1/12, 16.6%). The nature and type of
abnormalities differed among the cases. In the first case, what was
identified as a de novo t(9;15)(q31;q26.1), a complex rearrangement was
revealed involving a similar to 6.1 Mb duplication on the long arm of
chromosome 9, an similar to 10 Mb deletion and an inversion both on the
long arm of chromosome 15. These imbalances were located near the
translocation breakpoints. In the second case of a de novo
t(4;9)(q25;q21.2), an similar to 6.6 Mb deletion was identified on the
short arm of chromosome 7 which is unrelated to the translocation. In
the third case, of a familial, t(4; 7)(q13.3; p15.3), two deletions of
similar to 4.3 Mb and similar to 2.3 Mb were found, each at one of the
two translocation breakpoints. In the remaining cases the translocations
appeared balanced at 1 Mb resolution.
Conclusion: This study investigated both de novo and familial apparently
balanced translocations unlike other relatively large studies which are
mainly focused on de novo cases. This study provides additional evidence
that cryptic genomic imbalances are common in patients with abnormal
phenotype and “apparently balanced” translocations not only in de
novo but can also occur in familial cases. The use of microarrays with
higher resolution such as oligo-arrays may reveal that the frequency of
cryptic genomic imbalances among these patients is higher