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• Refining the critical region of the novel 19q13.11 microdeletion syndrome to 750 Kb.
  Bert B.A. De Vries
  Published on: 27 April 2016

• Published on: 27 April 2016

  Refining the critical region of the novel 19q13.11 microdeletion syndrome to 750 Kb.

  • Bert B.A. De Vries, clinical geneticist
  • Other Contributors:
    • Janneke H.M. Schuurs-Hoeijmakers, Sascha Vermeer, Bregje W.M. van Bon, Rolph Pfundt, Carlo Marcelis, Arjan P.M. de Brouwer, Nicole de Leeuw

  With great interest we read the article of Malan et al., who reported on a novel clinically recognizable 19q13.11 microdeletion syndrome.1 Here we report on a fifth patient with an interstitial deletion overlapping the 19q13.11 region and compare our findings with those described by Malan et al. The proband was born after 37 weeks of gestation as one of dizygotic twins with a birth weight of 1620 g (-3.5 SD). His twin sist...

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  With great interest we read the article of Malan et al., who reported on a novel clinically recognizable 19q13.11 microdeletion syndrome.1 Here we report on a fifth patient with an interstitial deletion overlapping the 19q13.11 region and compare our findings with those described by Malan et al. The proband was born after 37 weeks of gestation as one of dizygotic twins with a birth weight of 1620 g (-3.5 SD). His twin sister had a normal birth weight of 2290 g (p25). They were the first children of healthy non-consanguineous parents. Pregnancy was complicated by intrauterine growth retardation. At birth the proband had cutis aplasia over the posterior occiput, hypospadias, abnormal positioning of the feet, and a third nipple on the left side of the chest (the latter was also present in the father) whereas no dysmophisms where reported in his sister. During the first years of life, feeding difficulties, failure to thrive, and psychomotor delay were noted: he sat independently at two years of age, started crawling at the same age and started walking at the age of three years and ten months. Because of fatigue, he was able to walk short distances only, and walked with a stiff gait. He suffered from recurrent airway infections. At the age of four years and 10 months he could not speak, but was able to communicate with pictograms. He had hypermetropia (+3D/+4D) similar to his sister. At that age his height was 101.5 cm (-2.5 SD), weight was 15.4 kg (-0.5 SD), and head circumference was 45.5 cm (-3.5 SD). He had deep-set eyes, a broad nasal tip, a broad mouth with thin lips, broad gums, irregular placed teeth and retrognatia. Other features were long fingers with slender thumbs and long, dysplastic nails, a third nipple on the left side of the thorax, hypospadias, a sacral dimple and hyperlaxity of the joints (figure 1A-G).

  Routine cytogenetic analysis with GTG-banding and subsequent Multiplex Ligation Dependent Probe Amplification (MLPA) analysis of the subtelomeric regions did not reveal any abnormalities. Array based comparative genomic hybridisation analysis (~ 32.000 BAC clones with an average resolution of 300 kb) was performed as previously described (de Vries et al. 2005 2) and revealed a 2.4 Mb loss in 19q13.11q13.12 (39.5- 41.9 Mb) encompassing ~ 50 genes (46,XY.arr cgh 19q13.11q13.12(RP11-615P - > RP11-679B20)x1). This deletion was subsequently confirmed by region specific Fluorescence In Situ Hybridisation (FISH) analysis using three BAC clones which map to the aberrant region (46,XY.ish del(19)(q13.11.q13.12)(RP11_615P5-,RP11_233i16-,RP11_679B20-). In addition, high resolution 250K SNP array analysis (Affymetrix, Inc., Santa Clara, CA, USA; average practical resolution of 200 kb) was performed to further characterize the extend of the deletion (figure 1H). Both SNP array and FISH analysis were performed in the parents showing that the deletion occurred de novo, that the maternal allele was deleted in the proband and that the mother was carrier of an intrachromosomal, submicroscopic insertion on chromosome 19 (46,XX.ish ins(19)(q13.?3q13.11q13.12)(q13.11)(RP11_615P5-, RP11_223i16- )(q13.12)(RP11_679B20-) (q13.?3)(RP11_615P5+,RP11_223i16+, RP11_679B20+). Therefore, recombination during meiosis is the underlying mechanism for the deletion to occur in her son (data not shown).

  In addition to the report by Malan et al. and Kulharya et al., 3 this is the fifth patient with an interstitial deletion of the 19q13.11 region, overlapping the smallest region of overlap of the previously described patients by only 750 kb. Remarkably though, our patient shares several major features with the previously reported patients including intrauterine and postnatal growth retardation, primary microcephaly, speech disturbance, mental retardation, hypospadias and ectodermal dysplasia presented by scalp aplasia, dysplastic nails and a dry skin (table 1). The feeding problems in our patient did not seem to be as severe as in the patients described by Malan et al. No cardiac defects or deafness were noted, although the latter was only reported in the case with the large 11 Mb deletion.

  The deletion in the current patient narrows down the critical region for this novel microdeletion syndrome to ~ 750 Kb (B36.1:CHR19:39 378 624 - 40 131 974) containing only 11 RefSeq genes (NCBI RNA reference sequence collection 4,5) (figure 1I). For three genes, PDCD2L, KIAA0355, SCGBL, the function is unknown. The glucose phosphate isomerase gene (GPI; OMIM #172400) encodes a housekeeping cytosolic enzyme playing a major role in the glycolysis and the gluconeogenesis pathway. As GPI mutations cause autosomal recessive chronic hemolytic anemia it is not likely that haploinsuffiency of this gene contributes to the phenotype in this novel microdeletion syndrome.6,7,8 Wilms tumor 1 interacting protein (WTIP) is shown to interact with WT1, which is a zinc finger transcription factor. ZNF302, ZNF181, ZNF599 and ZNF30 are clustered on chromosome 19q13.11 and belong to the KRAB-ZNF subfamily. KRAB-ZNFs have been described as transcription repressors. ZNF clusters have expanded in the primate evolution lineage and are suspected to contribute to higher cognitive functioning in primates. 9,10 As three zinc finger genes have previously been shown to be involved in X-linked mental retardation in males, ZNF41, ZNF81, ZNF674, 11,12,13 it might be that haploinsuffiency of the zinc finger cluster in 19q13.11 is involved in the pathogenesis in this novel syndrome. LSM14A is a Sm-like protein with sequence homology with the Sm protein family. Sm-like proteins are evolutionary conserved in eukaryotes and are thought to have a fundamental role in control of mRNA translation making LSM14A a interesting candidate gene.14,15 Ubiquitin-like modifier activation enzyme 2 (UBA2) is playing a role in the ubiquitin pathway. Ubiquitin and ubiquitin-like modifiers regulate multiple important cellular processes: cell differentiation, apoptosis, posttranslational modification, transcriptional regulation and DNA repair and are known to be involved in mental retardation syndromes such as Angelman syndrome (OMIM#105830), Opitz syndrome (OMIM #300000), Bardet-Biedl syndrome (OMIM#209900) and limb-girdle muscular dystrophy type 2H (OMIM #254110).16,17

  As our patient has a similar phenotype as the patients described by Malan et al. and Kulharya et al. we narrowed down the critical region of this novel microdeletion syndrome from 2,87 Mb to 750 Kb encompassing 11 genes. It is very likely that haploinsufficiency of one or more genes in this region give rise to this microdeletion syndrome for which LSM14A and UBA2 seem the most promising candidates.

  J.H.M. Schuurs-Hoeijmakers, S. Vermeer, B.W.M. van Bon, R. Pfundt, C. Marcelis, A.P.M. de Brouwer, N. de Leeuw, B.B.A. de Vries Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

  Correspondence to: Bert B.A. de Vries, Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 (0) 243613946; fax: +31 (0) 243668753; e-mail: b.devries@antrg.umcn.nl

  Acknowledgements: We are sincerely appreciative to the patient and his parents for their support and cooperation. This work was supported by grants from the Netherlands Organisation for Health Research and Development (ZON-MW) (BBAdV), Hersenstichting Nederland (BBAdV), and grants from the AnEUploidy project (LSHG-CT-2006-037627) supported by the European Commission under FP6 (BBAdV, BvB). The authors wish to acknowledge the absence of any competing interest.

  Competing interest: None.

  Patient consent: Consent was obtained from the patient's family for publishing patient details and images in figure 1.

  References 1. Malan V, Raoul O, Firth HV, Royer G, Turleau C, Bernheim A et al. 19q13.11 deletion syndrome: a novel clinically recognizable genetic condition identified by array-CGH. J Med Genet. Epub 2009 Jan 6. 2. de Vries BB, Pfundt R, Leisink M, Koolen DA, Vissers LE, Janssen IM et al. Diagnostic genome profiling in mental retardation. Am J Hum Genet. 2005;77(4):606-16. 3. Kulharya AS, Michaelis RC, Norris KS, Taylor HA, Garcia-Heras J. Constitutional del(19)(q12q13.1) in a three-year-old girl with severe phenotypic abnormalities affecting multiple organ systems. Am J Med Genet. 1998;77(5):391-4. 4. Kent WJ. BLAT - the BLAST-like alignment tool. Genome Res. 2002;12(4):656-64. 5. Pruitt KD, Tatusova T, Maglott DR. NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 2005;33(Database issue):D501-4 6. Arnold H. Inherited glucosephosphate isomerase deficiency. A review of known variants and some aspects of the pathomechanism of the deficiency. Blut. 1979;39(6):405-17. Review. 7. Kanno H, Fujii H, Hirono A, Ishida Y, Ohga S, Fukumoto Y et al. Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia. Blood. 1996;88(6):2321-5 8. Kugler W, Breme K, Laspe P, Muirhead H, Davies C, Winkler H et al. Molecular basis of neurological dysfunction coupled with haemolytic anaemia in human glucose-6-phosphate isomerase (GPI) deficiency. Hum Genet. 1998;103(4):450-4 9. Urrutia R. KRAB-containing zinc-finger repressor proteins. Genome Biol. 2003;4(10):231. Review. 10. Emerson RO, Thomas JH. Adaptive evolution in zinc finger transcription factors. PLoS Genet. 2009;5(1):e1000325. Epub 2009 Jan 2. 11. Lugtenberg D, Yntema HG, Banning MJ, Oudakker AR, Firth HV, Willatt L, et al. ZNF674: a new kruppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation. Am J Hum Genet. 2006;78(2):265-78. 12. Kleefstra T, Yntema HG, Oudakker AR, Banning MJ, Kalscheuer VM, Chelly Jet al. Zinc finger 81 (ZNF81) mutations associated with X-linked mental retardation. J Med Genet 2004;41:394¡V399 13. Shoichet SA, Hoffmann K, Menzel C, Trautmann U, Moser B, Hoeltzenbein M et al. Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation. Am J Hum Genet 2003;73:1341¡V1354. 14. Marnef A, Sommerville J, Ladomery . RAP55: Insights into an evolutionarily conserved protein family. Int J Biochem Cell Biol. E pub 2008 Aug 3. 15. Yang WH, Yu JH, Gulick T, Bloch KD, Bloch DB. RNA-associated protein 55 (RAP55) localizes to mRNA processing bodies and stress granules. RNA. 2006;12(4):547-54. 16. Lois LM, Lima CD. Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1. EMBO J. 2005;24(3):439-51. 17. Li T, Santockyte R, Shen RF, Tekle E, Wang G, Yang DC, Chock PB. A general approach for investigating enzymatic pathways and substrates for ubiquitin-like modifiers. Arch Biochem Biophys. 2006;453(1):70-4.

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  Conflict of Interest:
  None declared.

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