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Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications

      Abstract

      Objective

      Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features.

      Method

      In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype–phenotype correlation among them was examined.

      Results

      We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes.

      Conclusion

      The genotype–phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8–2.1 and 1.8–2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype–phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.

      Keywords

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      References

        • Shapira S.K.
        • McCaskill C.
        • Northrup H.
        • Spikes A.S.
        • Elder F.F.B.
        • Sutton V.R.
        • et al.
        Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome.
        Am J Hum Genet. 1997; 61: 642-650
        • Gajecka M.
        • Yu W.
        • Ballif B.C.
        • Glotzbach C.D.
        • Bailey K.A.
        • Shaw C.A.
        • et al.
        Delineation of mechanisms and regions of dosage imbalance in complex rearrangements of 1p36 leads to a putative gene for regulation of cranial suture closure.
        Eur J Hum Genet. 2005; 13: 139-149
        • Heilstedt H.A.
        • Ballif B.C.
        • Howard L.A.
        • Lewis R.A.
        • Stal S.
        • Kashork C.D.
        • et al.
        Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome.
        Am J Hum Genet. 2003; 72: 1200-1212
        • Shao L.
        • Shaw C.A.
        • Lu X.Y.
        • Sahoo T.
        • Bacino C.A.
        • Lalani S.R.
        • et al.
        Identification of chromosome abnormalities in subtelomeric regions by microarray analysis: a study of 5,380 cases.
        Am J Med Genet A. 2008; 146A: 2242-2251
        • Heilstedt H.A.
        • Ballif B.C.
        • Howard L.A.
        • Kashork C.D.
        • Shaffer L.G.
        Population data suggest that deletions of 1p36 are a relatively common chromosome abnormality.
        Clin Genet. 2003; 64: 310-316
        • Slavotinek A.
        • Shaffer L.G.
        • Shapira S.K.
        Monosomy 1p36.
        J Med Genet. 1999; 36: 657-663
        • Battaglia A.
        • Hoyme H.E.
        • Dallapiccola B.
        • Zackai E.
        • Hudgins L.
        • McDonald-McGinn D.
        • et al.
        Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation.
        Pediatrics. 2008; 121: 404-410
        • Battaglia A.
        Del 1p36 syndrome: a newly emerging clinical entity.
        Brain Dev. 2005; 27: 358-361
        • Zenker M.
        • Rittinger O.
        • Grosse K.P.
        • Speicher M.R.
        • Kraus J.
        • Rauch A.
        • et al.
        Monosomy 1p36-a recently delineated, clinically recognizable syndrome.
        Clin Dysmorphol. 2002; 11: 43-48
        • Kurosawa K.
        • Kawame H.
        • Okamoto N.
        • Ochiai Y.
        • Akatsuka A.
        • Kobayashi M.
        • et al.
        Epilepsy and neurological findings in 11 individuals with 1p36 deletion syndrome.
        Brain Dev. 2005; 27: 378-382
        • Buck A.
        • du Souich C.
        • Boerkoel C.F.
        Minimal genotype–phenotype correlation for small deletions within distal 1p36.
        Am J Med Genet A. 2011; 155A: 3164-3169
        • Rosenfeld J.A.
        • Crolla J.A.
        • Tomkins S.
        • Bader P.
        • Morrow B.
        • Gorski J.
        • et al.
        Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions.
        Am J Med Genet A. 2010; 152A: 1951-1959
        • D’Angelo C.S.
        • Da Paz J.A.
        • Kim C.A.
        • Bertola D.R.
        • Castro C.I.E.
        • Varela M.C.
        • et al.
        Prader–Willi-like phenotype: investigation of 1p36 deletion in 41 patients with delayed psychomotor development, hypotonia, obesity and/or hyperphagia, learning disabilities and behavioral problems.
        Eur J Med Genet. 2006; 49: 451-460
        • Okamoto N.
        • Toribe Y.
        • Nakajima T.
        • Okinaga T.
        • Kurosawa K.
        • Nonaka I.
        • et al.
        A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy.
        J Hum Genet. 2002; 47: 556-559
        • Hiraki Y.
        • Fujita H.
        • Yamamori S.
        • Ohashi H.
        • Eguchi M.
        • Harada N.
        • et al.
        Mild craniosynostosis with 1p36.3 trisomy and 1p36.3 deletion syndrome caused by familial translocation t(Y;1).
        Am J Med Genet A. 2006; 140A: 1773-1777
        • Saito Y.
        • Kubota M.
        • Kurosawa K.
        • Ichihashi I.
        • Kaneko Y.
        • Hattori A.
        • et al.
        Polymicrogyria and infantile spasms in a patient with 1p36 deletion syndrome.
        Brain Dev. 2011; 33: 437-441
        • Shimada S.
        • Maegaki Y.
        • Osawa M.
        • Yamamoto T.
        Mild developmental delay and obesity in two patients with mosaic 1p36 deletion syndrome.
        Am J Med Genet A. 2014; 164A: 415-420
        • Shimada S.
        • Okamoto N.
        • Hirasawa K.
        • Yoshii K.
        • Tani Y.
        • Sugawara M.
        • et al.
        Clinical manifestations of Xq28 functional disomy involving MECP2 in one female and two male patients.
        Am J Med Genet A. 2013; 161A: 1779-1785
        • Shimada S.
        • Okamoto N.
        • Ito M.
        • Arai Y.
        • Momosaki K.
        • Togawa M.
        • et al.
        MECP2 duplication syndrome in both genders.
        Brain Dev. 2013; 35: 411-419
        • Kang S.H.
        • Scheffer A.
        • Ou Z.
        • Li J.
        • Scaglia F.
        • Belmont J.
        • et al.
        Identification of proximal 1p36 deletions using array-CGH: a possible new syndrome.
        Clin Genet. 2007; 72: 329-338
        • Shimojima K.
        • Paez M.T.
        • Kurosawa K.
        • Yamamoto T.
        Proximal interstitial 1p36 deletion syndrome: the most proximal 3.5-Mb microdeletion identified on a dysmorphic and mentally retarded patient with inv(3)(p14.1q26.2).
        Brain Dev. 2009; 31: 629-633
        • Benzing T.
        • Schermer B.
        Clinical spectrum and pathogenesis of nephronophthisis.
        Curr Opin Nephrol Hypertens. 2012; 21: 272-278
        • Otto E.A.
        • Ramaswami G.
        • Janssen S.
        • Chaki M.
        • Allen S.J.
        • Zhou W.
        • et al.
        Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy.
        J Med Genet. 2011; 48: 105-116
        • Gajecka M.
        • Mackay K.L.
        • Shaffer L.G.
        Monosomy 1p36 deletion syndrome.
        Am J Med Genet C. 2007; 145C: 346-356
        • Wu Y.Q.
        • Heilstedt H.A.
        • Bedell J.A.
        • May K.M.
        • Starkey D.E.
        • McPherson J.D.
        • et al.
        Molecular refinement of the 1p36 deletion syndrome reveals size diversity and a preponderance of maternally derived deletions.
        Hum Mol Genet. 1999; 8: 313-321
        • Colmenares C.
        • Heilstedt H.A.
        • Shaffer L.G.
        • Schwartz S.
        • Berk M.
        • Murray J.C.
        • et al.
        Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski−/− mice.
        Nat Genet. 2002; 30: 106-109
        • Heilstedt H.A.
        • Burgess D.L.
        • Anderson A.E.
        • Chedrawi A.
        • Tharp B.
        • Lee O.
        • et al.
        Loss of the potassium channel beta-subunit gene, KCNAB2, is associated with epilepsy in patients with 1p36 deletion syndrome.
        Epilepsia. 2001; 42: 1103-1111
        • Arndt A.K.
        • Schafer S.
        • Drenckhahn J.D.
        • Sabeh M.K.
        • Plovie E.R.
        • Caliebe A.
        • et al.
        Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
        Am J Hum Genet. 2013; 93: 67-77
        • Potts R.C.
        • Zhang P.
        • Wurster A.L.
        • Precht P.
        • Mughal M.R.
        • Wood III, W.H.
        • et al.
        CHD5, a brain-specific paralog of Mi2 chromatin remodeling enzymes, regulates expression of neuronal genes.
        PLoS One. 2011; 6: e24515
        • Neal J.
        • Apse K.
        • Sahin M.
        • Walsh C.A.
        • Sheen V.L.
        Deletion of chromosome 1p36 is associated with periventricular nodular heterotopia.
        Am J Med Genet A. 2006; 140: 1692-1695
        • Saito S.
        • Kawamura R.
        • Kosho T.
        • Shimizu T.
        • Aoyama K.
        • Koike K.
        • et al.
        Bilateral perisylvian polymicrogyria, periventricular nodular heterotopia, and left ventricular noncompaction in a girl with 10.5–11.1 Mb terminal deletion of 1p36.
        Am J Med Genet A. 2008; 146A: 2891-2897
        • Descartes M.
        • Mikhail F.M.
        • Franklin J.C.
        • McGrath T.M.
        • Bebin M.
        Monosomy1p36.3 and trisomy 19p13.3 in a child with periventricular nodular heterotopia.
        Pediatr Neurol. 2011; 45: 274-278
        • Dobyns W.B.
        • Mirzaa G.
        • Christian S.L.
        • Petras K.
        • Roseberry J.
        • Clark G.D.
        • et al.
        Consistent chromosome abnormalities identify novel polymicrogyria loci in 1p36.3, 2p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and 21q2.
        Am J Med Genet A. 2008; 146A: 1637-1654
        • Thienpont B.
        • Mertens L.
        • Buyse G.
        • Vermeesch J.R.
        • Devriendt K.
        Left-ventricular non-compaction in a patient with monosomy 1p36.
        Eur J Med Genet. 2007; 50: 233-236
        • Cremer K.
        • Ludecke H.J.
        • Ruhr F.
        • Wieczorek D.
        Left-ventricular non-compaction (LVNC): a clinical feature more often observed in terminal deletion 1p36 than previously expected.
        Eur J Med Genet. 2008; 51: 685-688
        • Gajecka M.
        • Saitta S.C.
        • Gentles A.J.
        • Campbell L.
        • Ciprero K.
        • Geiger E.
        • et al.
        Recurrent interstitial 1p36 deletions: evidence for germline mosaicism and complex rearrangement breakpoints.
        Am J Med Genet A. 2010; 152A: 3074-3083
        • Faivre L.
        • Morichon-Delvallez N.
        • Viot G.
        • Martinovic J.
        • Pinson M.P.
        • Aubry J.P.
        • et al.
        Prenatal detection of a 1p36 deletion in a fetus with multiple malformations and a review of the literature.
        Prenat Diagn. 1999; 19: 49-53
        • Riegel M.
        • Castellan C.
        • Balmer D.
        • Brecevic L.
        • Schinzel A.
        Terminal deletion, del(1)(p36.3), detected through screening for terminal deletions in patients with unclassified malformation syndromes.
        Am J Med Genet. 1999; 82: 249-253
        • Redon R.
        • Rio M.
        • Gregory S.G.
        • Cooper R.A.
        • Fiegler H.
        • Sanlaville D.
        • et al.
        Tiling path resolution mapping of constitutional 1p36 deletions by array-CGH: contiguous gene deletion or “deletion with positional effect” syndrome?.
        J Med Genet. 2005; 42: 166-171
        • Digilio M.C.
        • Bernardini L.
        • Lepri F.
        • Giuffrida M.G.
        • Guida V.
        • Baban A.
        • et al.
        Ebstein anomaly: genetic heterogeneity and association with microdeletions 1p36 and 8p23.1.
        Am J Med Genet A. 2011; 155A: 2196-2202
        • Sinkovec M.
        • Kozelj M.
        • Podnar T.
        Familial biventricular myocardial noncompaction associated with Ebstein’s malformation.
        Int J Cardiol. 2005; 102: 297-302
        • Sentex E.
        • Wang X.
        • Liu X.
        • Lukas A.
        • Dhalla N.S.
        Expression of protein kinase C isoforms in cardiac hypertrophy and heart failure due to volume overload.
        Can J Physiol Pharmacol. 2006; 84: 227-238
        • Wu S.C.
        • Solaro R.J.
        Protein kinase C zeta. A novel regulator of both phosphorylation and de-phosphorylation of cardiac sarcomeric proteins.
        J Biol Chem. 2007; 282: 30691-30698
        • Kim B.J.
        • Zaveri H.P.
        • Shchelochkov O.A.
        • Yu Z.
        • Hernandez-Garcia A.
        • Seymour M.L.
        • et al.
        An allelic series of mice reveals a role for RERE in the development of multiple organs affected in chromosome 1p36 deletions.
        PLoS One. 2013; 8: e57460
        • Barron D.J.
        • Kilby M.D.
        • Davies B.
        • Wright J.G.
        • Jones T.J.
        • Brawn W.J.
        Hypoplastic left heart syndrome.
        Lancet. 2009; 374: 551-564
        • Grossfeld P.D.
        The genetics of hypoplastic left heart syndrome.
        Cardiol Young. 1999; 9: 627-632
        • Sanchez-Valle A.
        • Pierpont M.E.
        • Potocki L.
        The severe end of the spectrum: hypoplastic left heart in Potocki–Lupski syndrome.
        Am J Med Genet A. 2011; 155A: 363-366
        • Chen C.P.
        • Chern S.R.
        • Hsu C.Y.
        • Lee C.C.
        • Lee M.S.
        • Wang W.
        Prenatal diagnosis of de novo partial trisomy 13q (13q22 → qter) and partial monosomy 8p (8p23.3 → pter) associated with holoprosencephaly, premaxillary agenesis, hexadactyly, and a hypoplastic left heart.
        Prenat Diagn. 2005; 25: 334-336
        • Tsuyusaki Y.
        • Yoshihashi H.
        • Furuya N.
        • Adachi M.
        • Osaka H.
        • Yamamoto K.
        • et al.
        1p36 deletion syndrome associated with Prader–Willi-like phenotype.
        Pediatr Int. 2010; 52: 547-550