A Rare, Recurrent, De Novo 14q32.2q32.31 Microdeletion of 1.1？Mb in a 20-Year-Old Female Patient with a Maternal UPD(14)-Like Phenotype and Intellectual Disability
We present a 20-year-old female patient from Indonesia with intellectual disability (ID), proportionate short stature, motor delay, feeding problems, microcephaly, facial dysmorphism, and precocious puberty who was previously screened normal for conventional karyotyping, fragile X testing, and subtelomeric MLPA analysis. Subsequent genome wide array analysis was performed on DNA from blood and revealed a 1.1？Mb deletion in 14q32.2q32.31 (chr14:100,388,343-101,506,214; hg19). Subsequent carrier testing in the parents by array showed that the deletion had occurred de novo in the patient and that her paternal 14q32 allele was deleted. The deleted region encompasses the DLK1/GTL2 imprinted gene cluster which is consistent with the maternal UPD(14)-like phenotype of the patient. This rare, recurrent microdeletion was recently shown not to be mediated by low copy repeats, but by expanded TGG repeats, flanking the 14q32.2q32.21 deletion boundaries, a novel mechanism of recurrent genomic rearrangement. This is another example how the application of high resolution genome wide testing provides an accurate genetic diagnosis, thereby improving the care for patients and optimizing the counselling for family. 1. Introduction The application of high resolution genome wide array analysis provides an accurate genetic diagnosis in many patients with ID and/or congenital anomalies caused by genomic imbalances. The use of this technology has led to the discovery of several novel microdeletion and microduplication syndromes. Although several patients have been reported with a terminal 14q32 deletion, patients with an in terstitial microdeletion in the 14q32 region seem to be rare. To our knowledge, only two patients with an interstitial 1.1？Mb deletion in q32.2q32.31 have previously been reported [1, 2]. Human chromosome 14q32.2 is the critical region for uniparental disomy of chromosome 14 (UPD(14)) phenotypes because it carries a cluster of imprinted genes, including the paternally expressed genes (PEGs) such as DLK1&RTL1 and the maternally expressed genes (MEGs) such as GTL2 (also known as MEG3), RTL1as (RTL1 antisense), and MEG8. Deletion of the paternal allele in this region causes a UPD(14)mat-like phenotype [3]. Uniparental disomy (UPD) occurs when the two copies of a chromosome pair are inherited from only one parent [4]. Maternal UPD of chromosome 14 (UPD(14)mat) is characterized by pre- and postnatal growth retardation, hypotonia, feeding problems, motor delay, short stature, early onset of puberty, and minor dysmorphic features of the face, hands, and feet [5].
References
[1]
F. Béna, S. Gimelli, E. Migliavacca et al., “A recurrent 14q32.2 microdeletion mediated by expanded TGG repeats,” Human Molecular Genetics, vol. 19, no. 10, pp. 1967–1973, 2010.
[2]
K. Buiting, D. Kanber, J. I. Martín-Subero et al., “Clinical features of maternal uniparental disomy 14 in patients with an epimutation and a deletion of the imprinted DLK1/GTL2 gene cluster,” Human Mutation, vol. 29, no. 9, pp. 1141–1146, 2008.
[3]
M. Kagami, Y. Sekita, G. Nishimura et al., “Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes,” Nature Genetics, vol. 40, no. 2, pp. 237–242, 2008.
[4]
E. Engel, “A new genetic concept: uniparental disomy and its potential effect, isodisomy,” American Journal of Medical Genetics, vol. 6, no. 2, pp. 137–143, 1980.
[5]
V. R. Sutton and L. G. Shaffer, “Search for imprinted regions on Chromosome 14: comparison of maternal and paternal UPD cases with cases of chromosome 14 deletions,” American Journal of Medical Genetics, vol. 93, pp. 381–387, 2000.
[6]
D. Mitter, K. Buiting, F. Von Eggeling et al., “Is there a higher incidence of maternal uniparental disomy 14 [upd(14)mat]? Detection of 10 new patients by methylation-specific PCR,” American Journal of Medical Genetics A, vol. 140, no. 19, pp. 2039–2049, 2006.
[7]
K. Hosoki, T. Ogata, M. Kagami, T. Tanaka, and S. Saitoh, “Epimutation (hypomethylation) affecting the chromosome 14q32.2 imprinted region in a girl with upd(14)mat-like phenotype,” European Journal of Human Genetics, vol. 16, no. 8, pp. 1019–1023, 2008.
[8]
A. Schneider, B. Benzacken, A. Guichet et al., “Molecular cytogenetic characterization of terminal 14q32 deletions in two children with an abnormal phenotype and corpus callosum hypoplasia,” European Journal of Human Genetics, vol. 16, no. 6, pp. 680–687, 2008.
[9]
U. Zechner, N. Kohlschmidt, G. Rittner et al., “Epimutation at human chromosome 14q32.2 in a boy with a upd(14)mat-like clinical phenotype,” Clinical Genetics, vol. 75, no. 3, pp. 251–258, 2009.
[10]
F. E. Mundhofir, T. I. Winarni, B. W. van Bon, et al., “A cytogenetic study in a large population of intellectually disabled Indonesians,” Genetic Test Molecular Biomarkers, vol. 16, pp. 412–417, 2012.
[11]
I. Yao, J. Iida, W. Nishimura, and Y. Hata, “Synaptic and nuclear localization of brain-enriched guanylate kinase-associated protein,” Journal of Neuroscience, vol. 22, no. 13, pp. 5354–5364, 2002.
[12]
L. E. L. M. Vissers, J. De Ligt, C. Gilissen et al., “A de novo paradigm for mental retardation,” Nature Genetics, vol. 42, no. 12, pp. 1109–1112, 2010.
[13]
Y. He and P. Casaccia-Bonnefil, “The Yin and Yang of YY1 in the nervous system,” Journal of Neurochemistry, vol. 106, no. 4, pp. 1493–1502, 2008.
[14]
P. J. Hastings, J. R. Lupski, S. M. Rosenberg, and G. Ira, “Mechanisms of change in gene copy number,” Nature Reviews Genetics, vol. 10, no. 8, pp. 551–564, 2009.
[15]
J. Rubnitz and S. Subramani, “The minimum amount of homology required for homologous recombination in mammalian cells,” Molecular and Cellular Biology, vol. 4, no. 11, pp. 2253–2258, 1984.
[16]
A. S. Waldman and R. M. Liskay, “Dependence of intrachromosomal recombination in mammalian cells on uninterrupted homology,” Molecular and Cellular Biology, vol. 8, no. 12, pp. 5350–5357, 1988.
[17]
K. Usdin, “NGG-triplet repeats form similar intrastrand structures: implications for the triplet expansion diseases,” Nucleic Acids Research, vol. 26, no. 17, pp. 4078–4085, 1998.
