- Case report
- Open Access
Pure interstitial dup(6)(q22.31q22.31) – a case report
© Sheth et al.; licensee BioMed Central. 2015
- Received: 11 November 2014
- Accepted: 17 January 2015
- Published: 31 January 2015
‘Pure’ interstitial duplication of chr6q is rare. The varying size of duplication encompassing 6q22.31 is associated with the expressivity of dysmorphism and autism. Here, we report a unique case with facial dysmorphism, developmental delay, complex neurological impairment and spasticity unrelated to autism. Genetic analysis by aCGH exhibited a 627–971 kb dup(6)(q22.31q22.31) encompassing TRDN and NKAIN2 genes. The presence of the duplication was confirmed by quantitative PCR in the proband and phenotypically normal parents. With the current techniques, we cannot exclude presence of a deleterious homozygous point mutation in the proband where each copy would have been inherited from both parents.
- Neurological impairment
Around 3.6% of the duplications observed in the DNA are mainly clustered within pericentromeric and subtelomeric regions . Genomic DNA with segmental duplications are likely to be 1–200 kb in size and carry a high probability of encompassing repetitive sequences and coding genes . Segmental duplication is described for all human chromosomes with slightly greater number of cases with maternal inheritance . Duplication of long arm of chromosome 6 (chr6q) is rare. Most cases represent co-existence of an unbalanced translocation with other chromosome(s) that lead to a terminal duplication of chr6q with a partial monosomy of other chromosome/s. However, ‘Pure interstitial duplication of chr6q’ encompassing the larger segment is reported only in a few cases that provide clearly defined phenotypes affiliated to it [4,5]. Cases involving 6q22.31 duplication with another segmental aneusomy had phenotypic manifestations that are more associated to the later and not 6q22.31 [6,7]. Current case report presents an unusual case that portrays facial dysmorphism, severe developmental delay, complex neurological impairment and spasticity with 627–971 kb interstitial dup(6)(q22.31q22.31) as a sole observable anomaly inherited from either of the parents.
Micro-deletions and micro-duplications are relatively rare events, which arise during spermatogenesis or oogenesis. They might pass down disproportionately only for a few generations. They have been assigned to the ‘hotspot regions of the genome’ and are observed in several genetic disorders such as mental retardation (MR), developmental delay, schizophrenia, autism, neurocognitive disorders etc. [9,10]. Partial duplication of 6q with phenotypic alterations is reported only in few cases [5,11]. These reports showed that the duplication of 6q co-exist with other chromosomal abnormalities (chr16p and others) [6,7] where duplications were more common than deletions. Furthermore, the size of duplication is in direct correlation with the expression of clinical phenotypes. Scant reports of ‘Pure interstitial duplication of 6q’ are available in the literature [4,5]. The associated clinical features reported in most cases were intrauterine growth retardation (IUGR), hypertelorism, moderate facial dysmorphia (flat or depressed nasal bridge and anteverted nares), microcephaly, moderate psychomotor retardation, short fingers and cardiac anomaly linked to a varying degree of large sized duplication encompassing 6q22.31 . The present case had a relatively smaller interstitial duplication (~0.62 Mb) and presented almost all of the above clinical features except cardiac anomaly. Furthermore, the proband had severe developmental and intellectual disability and spasticity. He was neither able to sit, speak, stand nor walk without external support at the age of the presentation. However, the younger sibling with all of the above phenotypic features died at the age of 1 year. No investigations were carried out in the younger sibling. Goh et al.  found similar features in dysmorphic siblings, which were trisomic for 6q22.1 to 6q23.3, representing a large duplication.
Sanders et al.  reported multiple recurrent de novo duplications that were strongly associated with autism. At least 8 patients were reported to harbour duplications in 6q22.31 region ranging from 0.03 to 0.62 Mb along with the other concurrent segmented aneusomy . However, the patient presented in this report had a duplication of 0.62 Mb (627–971 kb; chr6:123,581,324‐124,208,360), only nearer to the previously reported regions. This region spans at least two genes (TRDN and NKAIN2), the entire coding region of TRDN  and the first exon of NKAIN2. TRDN (Triadin; OMIM No. 603283) with its alternatively spliced isoforms and differential expression is involved in excitation-contraction coupling of smooth and cardiac muscles as part of the calcium release complex in association with the ryanodine receptor. It has functions of (i) ion channel binding, (ii) protein binding and bridging, (iii) protein homo-dimerization activity and (iv) receptor binding functions. NKAIN2 (Na+/K+ Transporting ATPase-interacting 2; OMIM No. 609758) is a trans-membrane protein that interacts with the beta subunit of a sodium/potassium-transporting ATPase. Truncation of NKAIN2 has been described in patients with developmental delay  and complex neurological impairment . The interstitial duplication detected in the present case could have been inherited from either of the parents.
Since both parents were phenotypically normal, it is highly likely that the proband has a homozygous deleterious point mutation, giving rise to the phenotypic expression of severe developmental, intellectual disability and spasticity. This hypothesis could be further supported by the observation of Froyen et al. in their study of 300 families with X-linked mental retardation (XLMR) identifying 6 overlapping duplications of about 320 kb involving four genes (SMC1A, RIBC1, HSD17B10, HUWE1) encompassing Xp11.2 in unrelated males . In addition to the duplication, point mutation in SMC1A was shown to be associated with Cornelia de Lange syndrome with facial dysmorphism, mental retardation and growth deficit in childhood . The syndromic form of mental retardation with choreoathetosis was shown to be associated with silent mutation in HSD17B10 . Moreover, point mutations of HUWE1 gene leading to dose sensitisation may also partially be responsible for the phenotypes in cases with gene duplications, as shown by Froyen et al. .
Thus, the portrayed identical phenotype with severe morphological features presented here with relatively smaller pure interstitial dup(6)(q22.31q22.31) may additionally harbour deleterious point mutation, imparting a biologically pronounced effect which may be attributed to the high degree of consanguinity between parents.
Written informed consent was obtained from the parents of the patient for publication of this Case Report and accompanying images.
The authors acknowledge Dr. Chaitanya Datar and Dr. Petit Florence for help in deciphering clinical features. Our thanks are due to Mr. Harsh Sheth for critical reading of the manuscript. We also thank the patient and the parents for their consent.
- Bailey JA, Yavor AM, Massa HF, Trask BJ, Eichler EE. Segmental duplications: organization and impact within the current human genome project assembly. Genome Res. 2001;11(6):1005–17. doi:10.1101/gr.187101.View ArticlePubMed CentralPubMedGoogle Scholar
- IHGSC (International Human Genome Sequencing Consortium). Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921. doi:10.1038/35057062.View ArticleGoogle Scholar
- Kotzot D, Martinez MJ, Bagci G, Basaran S, Baumer A, Binkert F, et al. Parental origin and mechanisms of formation of cytogenetically recognizable de novo direct and inverted duplications. J Med Genet. 2000;37:281–6. doi:10.1136/jmg.37.4.281.View ArticlePubMed CentralPubMedGoogle Scholar
- Goh Denise LM, Tan Arnold SC, Chen Jean YC, Van den Berghe JA. Dysmorphic sibs trisomic for the region 6q22.1-6q23.3. J Med Genet. 2000;37:889–92. doi:10.1136/jmg.37.11.889.View ArticleGoogle Scholar
- Pazooki M, Lebbar A, Roubergues A, Baverel F, Letessier D, Dupont JM. Pure familial 6q21q22.1 duplication in two generations. Eur J Med Genet. 2007;50(1):60–5. doi:10.1016/j.ejmg.2006.09.002.View ArticlePubMedGoogle Scholar
- Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, et al. Multiple recurrent de novo copy number variations (CNVs), including duplications of the 7q11.23 Williams-Beuren syndrome region, are strongly associated with autism. Neuron. 2011;70(5):863–85. doi:10.1016/j.neuron.2011.05.002.View ArticlePubMed CentralPubMedGoogle Scholar
- Newbury DF, Mari F, Akha SE, MacDermot KD, Canitano R, Monaco AP, et al. Dual copy number variants involving 16p11 and 6q22 in a case of childhood apraxia of speech and pervasive developmental disorder. Eur J Hum Genet. 2013;21:361–5. doi:10.1038/ejhg.2012.166.View ArticlePubMed CentralPubMedGoogle Scholar
- Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, et al. Detection of large-scale variation in the human genome. Nat Genet. 2004;36:949–51. doi:10.1038/ng1416.View ArticlePubMedGoogle Scholar
- Eichler EE. Copy Number Variation and Human Disease. Nat Education. 2008;1(3):1.Google Scholar
- Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, et al. A recurrent 16p12.1 microdeletion suggests a two-hit model for severe developmental delay. Nat Genet. 2010;42(3):203–9. doi:10.1038/ng.534.View ArticlePubMed CentralPubMedGoogle Scholar
- Zneimer SM, Ziel B, Bachman R. Partial trisomy of chromosome 6q: an interstitial duplication of the long arm. Am J Med Genet. 1998;80:133–5. doi:10.1002/(SICI)1096-8628(19981102)80:2<133::AID-AJMG8>3.0.CO;2-B.View ArticlePubMedGoogle Scholar
- Taske’ NL, Eyre HJ, O’brien’ RO, Sutherland GR, Denborough’ MA, Foster’ PS. Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23. Eur J Biochem. 1995;233:258–65. doi:10.1111/j.1432-1033.1995.258_1.x.View ArticleGoogle Scholar
- Yue Y, Stout K, Grossmann B, Zechner U, Brinckmann A, White C, et al. Disruption of TCBA1 associated with a de novo t(1;6)(q32.2;q22.3) presenting in a child with developmental delay and recurrent infections. J Med Genet. 2006;43:143–7. doi:10.1136/jmg.2004.029660.View ArticlePubMed CentralPubMedGoogle Scholar
- Bocciardi R, Giorda R, Marigo V, Zordan P, Montanaro D, Gimelli S, et al. Molecular characterization of a t(2;6) balanced translocation that is associated with a complex phenotype and leads to truncation of the TCBA1 gene. Hum Mut. 2005;26(5):426–36. doi:10.1002/humu.20235.View ArticlePubMedGoogle Scholar
- Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, et al. Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am J Hum Genet. 2008;82:432–43. doi:10.1016/j.ajhg.2007.View ArticlePubMed CentralPubMedGoogle Scholar
- Musio A, Selicorni A, Focarelli ML, Gervasini C, Milani D, Russo S, et al. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet. 2006;38:528–30. doi:10.1038/ng1779.View ArticlePubMedGoogle Scholar
- Lenski C, Kooy RF, Reyniers E, Loessner D, Wanders RJ, Winnepenninckx B, et al. The reduced expression of the HADH2 protein causes X-linked mental retardation, choreoathetosis, and abnormal behavior. Am J Hum Genet. 2007;80:372–7. doi:10.1086/511527.View ArticlePubMed CentralPubMedGoogle Scholar
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