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Monday, 30 December 2019

DIAGNOSIS OF CHROMOSOME 4 LONG ARM MICRODELETION SYNDROME BY ARRAY-CGH

Written by Jorge Paco Ferreira | Ramón Giné Benaiges | Alfredo Santana Rodríguez

Figure 1. Karyotype (GTG bands). The breakpoints points on the two chromosomes involved in the translocation are indicated with arrows.

We report a clinical case of a pregnant woman, through IVF, of 40 years old referred to the Clinical Genetics Unit of the Clinical Analysis and Clinical Biochemistry Service of Maternal and Child Insular University Hospital Complex of Las Palmas de Gran Canaria, due to the pregnant woman´s advanced age.
A cytogenetic study is carried out for prenatal diagnosis from foetal cell cultures from amniotic fluid.

In the metaphases analyzed, with a resolution of 400 bands (G bands), a seemingly balanced reciprocal translocation is observed between the long arm on chromosome 4 pair and on the long arm on chromosome 11. Once the karyotypes of both parents were analysed, de novo translocation was confirmed: 46, XX, t (4; 11) (q35; q21)dn (figure 1).

Since no malformations are observed in the ultrasound follow-up, it is decided to continue the pregnancy assuming an average empirical risk of 6-10% of producing significant functional abnormalities or deficits in the foetus1.

In the initial exploration after birth, it was detected the presence of a hypotonic syndrome and multiple dysmorphic features accompanied by non-compacted cardiomyopathy. To investigate in greater depth the cut-off points of both translocated chromosomes (4 and 11) by means of a Comparative Genomic Hybridization (array-CGH) approach is decided. A complete genome platform (180K + SNP, Agilent) with an average resolution of 80Kb and 20Kb in target regions was chosen.

Following the ISCN-2016 formulation, the following anomalies were identified (figure 2):
4q31.3 (152202461_153962926) x1, 4q33q34.3
(171838421_178341384) x1.

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Figure 2. Results of the array-CGH showing the double microdeletion of chromosome 4. Within the rectangles of each microdeletion, some of the genes included in them are listed.
 
The patient was diagnosed of a Chromosome 4 Microdeletion Syndrome. After searching multiple clinical databases, several patients with similar microdeletions are identified; registered patients have moderate mental retardation (IQ 30-50), limited limb movements, swallowing problems, epilepsy as well as other traits and signs that they share with our patient2.

Among the genes contained in the microdeletion include:
  • HAND2 (OMIM 602407): cardiac transcription factor. Its deletion is associated with facial dysmorphic signs and non-compacted heart disease also presented by our patient3.
  • GPM6A (OMIM 601275): protein product specifically expressed in neurons4.
Some chromosomal abnormalities are not large enough to be visible at the cytogenetic level. Submicroscopic deletions can contain a single gene or affect several very close genes called Microdeletion or contiguous genes Syndromes. Most cases are sporadic.

Array-CGH is a very powerful diagnostic approach, although it is not widely used in the prenatal setting. Faced with specific clinical situations and, as long as it is performed and interpreted by expert professionals, it can provide very important data in the diagnosis and prognosis of patients. It is also a vital tool for the identification of new chromosomal abnormalities or syndromes not yet described.

The case described reveals that, given the identification of apparently balanced reciprocal translocations, by means of prenatal karyotype (de novo or inherited), the use of array-CGH as a complementary tool is justified. This diagnostic refinement allows to identify the possible presence of submicroscopic alterations, regardless of the ultrasound findings. The information provided is crucial for adequate genetic counselling and clinical decision making5.


References

  1. Aristidou C, Koufaris C, Theodosiou A, Bak M, Mehrjouy MM, Behjati F, et al. Accurate breakpoint mapping in apparently balanced translocation families with discordant phenotypes using whole genome mate-pair sequencing. PLoS One. 2017;12(1).
  2. Gonzalez C, Serrano MG, Barbancho Lopez C, Garcia-Riaño T, Barea Calero V, Moreno Perea R, et al. CGH Array and Karyotype as Complementary Tools in Prenatal Diagnosis: Prenatal Diagnosis of a 4q Derivative Chromosome from Maternal 4q;11q Translocation. Fetal Pediatr Pathol. 2018;37(3):184–90.
  3. Srivastava D, Thomas T, Kirby ML, Brown D, Olson EN. Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nat Genet. 1997;16(2):154–60.
  4. Olinsky S, Loop BT, DeKosky A, Ripepi B, Weng W, Cummins J, et al. Chromosomal mapping of the human M6 genes. Genomics [Internet]. 1996 May 1 [cited 2019 Jul 8];33(3):532–6. Available from: https://www.sciencedirect.com/science/article/pii/S0888754396902311?via%3Dihub
  5. Suela J, López-Expósito I, Querejeta ME, Martorell R, Cuatrecasas E, Armengol L, et al. Recommendations for the use of microarrays in prenatal diagnosis. Med Clin (Barc). 2017 Apr 7;148(7):328.e1-328.e8.

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