Partial Monosomy 21 (Q11.2→Q21.3) Combined with 3P25.3→Pter Monosomy Due to an Unbalanced Translocation in a Patient Present

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Gene 513 (2013) 301–304

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Short Communication Partial monosomy 21 (q11.2→q21.3) combined with 3p25.3→pter monosomy due to an unbalanced translocation in a patient presenting dysmorphic features and developmental delay

Ana Paula dos Santos, Társis Paiva Vieira, Milena Simioni, Fabíola Paoli Monteiro, Vera Lúcia Gil-da-Silva-Lopes ⁎

Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, UNICAMP, Campinas, SP, Brazil

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Article history: We describe a female patient of 1 year and 5 months-old, referred for genetic evaluation due to neuropsychomotor Accepted 3 September 2012 delay, hearing impairment and dysmorphic features. The patient presents a partial chromosome 21 monosomy Available online 29 September 2012 (q11.2→q21.3) in combination with a chromosome 3p terminal monosomy (p25.3→pter) due to an unbalanced de novo translocation. The translocation was confirmed by fluorescence in situ hybridization (FISH) and the Keywords: breakpoints were mapped with high resolution array. After the combined analyses with these techniques the final Partial monosomy 21 karyotype was defined as 45,XX,der(3)t(3;21)(p25.3;q21.3)dn,-21.ish der(3)t(3;21)(RP11-329A2-,RP11-439F4-, 3p25.3→pter monosomy Unbalanced translocation RP11-95E11-,CTB-63H24+).arr 3p26.3p25.3(35,333-10,888,738))×1,21q11.2q21.3(13,354,643-27,357,765)×1. Dysmorphic features and developmental Analysis of microsatellite DNA markers pointed to a paternal origin for the chromosome rearrangement. This delay is the first case described with a partial proximal monosomy 21 combined with a 3p terminal monosomy due to a de novo unbalanced translocation. © 2012 Elsevier B.V. Open access under the Elsevier OA license.

1. Introduction 21 monosomy (Keren et al., 2007). By the other way, 3p terminal deletions are related to variable clinical features (Malmgren et al., Partial deletion of chromosome 21 is a rare condition that has 2007). been associated with dysmorphic features, heart defects, seizures, de- Here we describe a female patient carrying a partial chromosome 21 layed motor function and mental retardation. Proximal 21q deletions monosomy (q11.2→q21.3) in combination with a chromosome 3p ter- often occur with segmental aneuploidy of other chromosomes, a con- minal monosomy (p25.3→pter) due to an unbalanced translocation. dition that makes the precise identification of segments involved dif- ficult (Lindstrand et al., 2010; Riegel et al., 2005). Full monosomy 21 2. Clinical report is probably not compatible with life, and some reports that have been published without molecular confirmation most likely represent The proband is a 1 year and 5 months-old girl, referred for genetic cryptic unbalanced translocations or mosaics (Riegel et al., 2005). evaluation for neuropsychomotor delay, hearing impairment and Rare cases of complete monosomy 21 prenatally diagnosed that sur- dysmorphic features. She is the second daughter born from non- vived to term were followed by early neonatal death (Mori et al., consanguineous parents (father — 39 years old / mother — 29 years 2004). There is not a recognized facial phenotype associated with old). Family history revealed a maternal half-sister and a maternal half-brother apparently healthy, and a maternal aunt with hearing loss and absence of language (not examined). Pregnancy was un- eventful. She was delivered at term by cesarean section; her birth Abbreviations: Ter, terminal; FISH, fluorescence in situ hybridization; BERA, weight was 2240 g (below the third centile), birth length was Brainstem Evoked Response Audiometry; TSH, thyroid stimulating hormone; FSH, fol- 41 cm (below the third centile) and head circumference was 31 cm licle stimulating hormone; FT4, free thyroxine; LH, luteinizing hormone; BAC, bacterial fi artificial chromosome; APP, Amyloid Beta (A4) Precursor Protein; SOD1, Cu/Zn super- (also below the third centile). During her rst year of life, she showed oxide dismutase; SRGAP3, SLIT-ROBO Rho GTPase activating protein 3; CNTN4, developmental delay and failure to thrive. contactin 4; CHL1, cell adhesion molecule with homology to L1CAM; CRBN, cereblon; Upon evaluation her weight was 6700 g (below the third centile ATP2B2, ATPase Ca+2 transporting plasma membrane 2. and corresponding to 5 months of age), length was 68 cm (below ⁎ Corresponding author at: Department of Medical Genetics, University of Campinas, the third centile and corresponding to 7.5 months of age), and head Tessália Vieira de Camargo Street, 126 - CEP 13083-887, Campinas, SP, Brazil. Tel.: +55 19 3521 8909. circumference was 40 cm (also below the third centile and corre- E-mail address: [email protected] (V.L. Gil-da-Silva-Lopes). sponding to 3 months of age), denoting an important failure to thrive.

Fig. 1. A): Patient's picture showing facial dysmorphisms, including arched eyebrows with medial flare, up-slanting palpebral fissures, blepharophimosis, bilateral ptosis, wide and depressed nasal bridge, bulbous tip of nose, anteverted nostrils, down-turned corners of the mouth and thin lips. B): Picture of patient's hands showing spindle-shaped fingers, mild lymphedema of hands and mildly dorsiflexed great toes.

Her physical examination disclosed besides microcephaly, mild flat to manufacturer's instructions. Data were analyzed by the Affymetrix occiput, bi-temporal narrowing, wide anterior fontanelle, low poste- Genotyping console 4.0 software (Affymetrix®, Santa Clara, CA, USA). rior hairline, bilateral pre-auricular pits, arched eyebrows with medi- Array analysis showed a deletion from 3p25.3 to 3p26.3 region with al flare, up-slanting palpebral fissures, blepharophimosis, bilateral approximately 10.8 Mb (breakpoints: 35,333-10,888,738 bp- NCBI Build ptosis, hypertelorism, wide and depressed nasal bridge, bulbous tip 36.1 [hg18]) (Fig. 3A) and a deletion from 21q11.2 to 21q21.3 region of nose, anteverted nostrils, down-turned corners of the mouth, thin with approximately 14.0 Mb (break points: 13,354,643-27,357,765 bp lips, long and smooth philtrum, mild retrognathia, wide hands with (NCBI Build 36.1 [hg18]) (Fig. 3B). The final karyotype was defined as spindle-shaped fingers, bilateral incomplete palmar creases, mild follow: 45,XX,der(3)t(3;21)(p25.3;q21.3)dn,-21.ish der(3)t(3;21) lymphedema of hands and feet, mildly dorsiflexed great toes and sa- (RP11-329A2-,RP11-439F4-,RP11-95E11-,CTB-63H24+).arr cral dimple (Fig. 1) (Supplementary Fig. 1). 3p26.3p25.3(35,333-10,888,738)×1,21q11. During evaluation, ophthalmologic examination, lumbosacral 2q21.3(13,354,643-27,357,765)×1. X-ray, transfontanellar ultrasound, abdominal ultrasound and echo- Analysis of microsatellite DNA markers was performed by auto- cardiogram disclosed no alterations. Brainstem Evoked Response matic genotyping. Markers mapped inside the deleted regions Audiometry (BERA) showed moderate hearing loss in both ears, though (D3S1297, D3S1304 and D21S1256) were selected from ABIPRISM not suggestive of cochlear nerve and auditory pathways involvement. Linkage Mapping set v. 2.5-HD5 (Applied Biosystems®). Genotyping Serum exams – TSH (thyroid stimulating hormone), FSH (follicle stim- was performed by polymerase chain reaction and products were ulating hormone), FT4 (free thyroxine), 17-OH-progesterone (17alpha- subsequently separated by capillary electrophoresis on Applied hydroxyprogesterone), LH (luteinizing hormone), free and conjugated Biosystems 3500xl Genetic Analyzer® (Applied Biosystems®). The testosterone values – were within normal limits. marker D21S1256 was uninformative. Loss of heterozygosity was found for markers D3S1297 and D3S1304 of chromosome 3 (data not shown). Only the maternal allele was observed in the proband, 3. Methods and results pointing to a paternal origin for the chromosome rearrangement.

3.1. Cytogenetics and FISH 4. Discussion The karyotype analysis of the patient revealed a missing chromosome 21 and an additional segment on the short arm of chromosome To date, at least 15 cases of unbalanced translocations giving rise 3 in 50 analyzed metaphases (Fig. 2A). The karyotypes of both parents to partial monosomy 21 have been reported involving different chro- were normal. mosomes such as 4, 5, 7, 11, 17, 18 and X (Cardoso et al., 2008; FISH was performed using BAC clones as previously described Hannachi et al., 2011; Riegel et al., 2001, 2005; Vorsanova et al., (Freitas et al., 2011). A subtelomere probe for the long arm of chro- 2008). To our knowledge this is the first case described with a partial mosome 21 (CTB-63H24 - 21q22.3-47943440-48100495 — assembly monosomy 21 combined with 3p monosomy due to a de novo unbal- GRCh37) was used and confirmed the presence of material from chro- anced translocation. mosome 21 on the derivative chromosome 3 (Fig. 2B). Additional BAC A probable mechanism of origin for this rearrangement could be a probes were used (RP11-329A2, RP11-439F4 and RP11-95E11 mapped reciprocal translocation followed by 3:1 segregation during meiosis. at 3p; RP11-102E10, RP11-410P24 and RP11-132H24 mapped at 21q), This mechanism is named 3:1 segregation with tertiary monosomy, which confirmed the rearrangement and revealed 3p terminal and which is fairly uncommon – at least in a term pregnancy – and may 21q proximal deletions (data not shown). arise only if one derivative is very small, and the amount of material that is missing is “monosomically small” (Gardner et al., 2012). In the case presented here only 3p distal and 21q proximal segments 3.2. Array and microsatellite DNA marker analyses are missing. The parental origin of the translocation in the present case was de- High resolution array was performed using the Genome-Wide termined to be paternal, which is in accordance with the literature Human SNP Array 6.0 (Affymetrix®, Santa Clara, CA, USA) according concerning structural chromosome rearrangements. The increased A.P. Santos et al. / Gene 513 (2013) 301–304 303

Fig. 2. A): Partial karyotype showing the derivative chromosome 3 and a chromosome 21 monosomy. The arrow points to additional chromosome material on the short arm of chromosome 3. B): FISH analysis on metaphase spreads with BAC CTB-63 H24 (21q22.3-47943440-48100495 — assembly GRCh37), showing one signal on a chromosome 21 and another signal on the derivative chromosome 3. frequency of chromosomal breaks and/or the presence of acentric frag- (Cardoso et al., 2008; Hattori et al., 2000). Monosomy of chromosome ments can be inﬂuenced by age in men. However, the impact of paternal 21, including APP (Amyloid Beta (A4) Precursor Protein) and SOD1 age on gametogenesis is still not well understood (Templado et al., (Cu/Zn superoxide dismutase) genes, was previously described in a 2011). In this family, the father is young and there is no history of risk patient with clinical features such as facial anomalies, hypertonia, factors for abnormal gametogenesis. mental retardation and arthrogryposis (Hannachi et al., 2011). The Some authors suggested that the proximal half of 21q contains 58 region deleted in our patient encompasses only APP gene. genes and, as consequence, rearrangements involving this region are Beyond 21q11.2→q21.3 deletion of approximately 14.0 Mb, the possibly more tolerable than rearrangements involving distal region patient here described also presents a deletion at 3p25.3→p26.3

Fig. 3. A) Array profile of chromosome 3. The circle highlights the 10.8 Mb deletion at p25.3–>p26.3 region. B) Array profile of chromosome 21. The circle highlights the 14.0 Mb deletion at q11.2–>q21.3 region. 304 A.P. Santos et al. / Gene 513 (2013) 301–304 region with approximately 10.8 Mb. Terminal deletion of chromosome the family of the patient. This work was supported with funding 3p25–3p26 are related to variable clinical features such as developmen- from the CNPq — Conselho Nacional de Desenvolvimento Científico tal and growth delay, multiple dysmorphisms, telecanthus, ptosis, men- e Tecnológico and FAPESP — Fundação de Amparo à Pesquisa do tal retardation, micrognathia, micro-and brachycephaly, hypertelorism, Estado de São Paulo, Brazil. low ears, postaxial polydactyly, renal anomalies, cleft palate, congenital heart defects and gastrointestinal anomalies (Cuoco et al., 2011; Dundar References et al., 2010; Gijsbers et al., 2010). Keren et al. 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Partial monosomy 7q34-qter and 21pter-q22.13 due to The authors gratefully acknowledge Professor Carla Rosenberg for cryptic unbalanced translocation t(7;21) but not monosomy of the whole chromo- providing the BAC probes used in this work. We are also grateful to some 21: a case report plus review of the literature. Mol. Cytogenet. 19 (1), 13.