Genotype-phenotype analysis of 4q deletion syndrome: Proposal of a critical region

Institute of Human Genetics, Newcastle upon Tyne, United Kingdom.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 09/2012; 158A(9):2139-51. DOI: 10.1002/ajmg.a.35502
Source: PubMed


Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a ∼465 kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes.

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    • "The most frequently detected clinical manifestations include mild to moderate intellectual disability, learning disabilities and minor dysmorphic features [Cingoz et al., 2006]. There are only a few reports in which array-CGH analysis were conducted to delineate a genotype–phenotype correlation in chromosome 4 long arm deletions [Strehle et al., 2012]. To the best of our knowledge, no previous reports exist of cytogenetically detectable familial chromosome 4 long arm deletions which are not accompanied by any discernible phenotypic effects. "
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    ABSTRACT: Small deletions on the long arm of distal chromosome 4 do not appear to result in gross congenital malformations, with the most frequently reported clinical findings including mild to moderate intellectual disability, learning disabilities and minor dysmorphic features. Here we report on a cytogenetically detectable familial interstitial chromosome 4 long arm deletion with no discernible phenotypic effects in a mother and her two daughters. The karyotypes of the mother and her two daughters were: 46,XX,del(4)(q35.1q35.2). Based on the results of FISH analyses using whole chromosome specific and subtelomeric probes, the karyotype was designated as: 46,XX,del(4)(q35.1q35.2). ish del(4)(q35-qter)(WCP4+, 36P21+, dJ963K6-). Array-CGH analysis showed an interstitial deletion encompassing 5.75 Mb in the 4q35.1-q35.2 genomic region (chr4:184,717,878-190,469,337; hg19). This is the first report on a cytogenetically detectable familial interstitial chromosome 4 long arm deletion in which there are no discernible phenotypic effects. Both our findings and a review of the literature suggest that more detailed molecular analyses are needed in cases with distal chromosome 4 long arm deletions especially those with breakpoints in the 4q35 region to establish a more precise genotype-phenotype correlation. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2015; 167(8). DOI:10.1002/ajmg.a.37097 · 2.16 Impact Factor
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    • "A number of patients have been reported with duplications and deletions of chromosome 4q33, the chromosomal region containing HAND2. Patients with both duplications and deletions have a high incidence of congenital heart defects including tetralogy of Fallot consistent with dosage sensitivity for this gene in human cardiogenesis but all duplications and deletions have affected multiple genes [29], [30]. "
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    ABSTRACT: Objective Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF). Methods and Results We sequenced the coding, 5′UTR, and 3′UTR regions of twelve transcription factor genes implicated in cardiac outflow tract development (NKX2.5, GATA4, ISL1, TBX20, MEF2C, BOP/SMYD1, HAND2, FOXC1, FOXC2, FOXH, FOXA2 and TBX1) in 93 non-syndromic, non-Mendelian TOF cases. We also analysed Illumina Human 660W-Quad SNP Array data for copy number variants in these genes; none were detected. Four of the rare variants detected have previously been shown to affect transactivation in in vitro reporter assays: FOXC1 p.P297S, FOXC2 p.Q444R, FOXH1 p.S113T and TBX1 p.P43_G61del PPPPRYDPCAAAAPGAPGP. Two further rare variants, HAND2 p.A25_A26insAA and FOXC1 p.G378_G380delGGG, A488_491delAAAA, affected transactivation in in vitro reporter assays. Each of these six functionally significant variants was present in a single patient in the heterozygous state; each of the four for which parental samples were available were maternally inherited. Thus in the 93 TOF cases we identified six functionally significant mutations in the secondary heart field transcriptional network. Significance This study indicates that rare genetic variants in the secondary heart field transcriptional network with functional effects on protein function occur in 3–13% of patients with TOF. This is the first report of a functionally significant HAND2 mutation in a patient with congenital heart disease.
    PLoS ONE 08/2014; 9(8):e95453. DOI:10.1371/journal.pone.0095453 · 3.23 Impact Factor
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    • "Expressed in the right side of the heart – associated with congenital heart defects 4q34.1 Russell et al., 1998; Middlemiss et al., 2011 BMP3 Associated with bone development – may be important for growth, since many children have short stature 4q21.21 Canalis et al., 2003; Middlemiss et al., 2011; Strehle et al., 2012 FGF2 Encodes a protein of the fibroblast growth factor family which has mitogenetic and angiogenetic properties 4q27 Kim et al., 1998; Middlemiss et al., 2011; Strehle et al., 2012 ABCE1 (RNS4I) Blocks the activity of ribonuclease L 4q31.22 Bisbal et al., 1995; Strehle et al., 2012; Tian et al., 2012 OTUD4 Expressed at the highest levels in lung, with high levels also detected in testis, ovary, kidney, skeletal muscle, liver, heart, brain, and fetal liver 4q31.22 Kikuno et al. 1999; Strehle et al., 2012 SMAD1 Represents the prototype of a large family of signal transducers and transcriptional modulators regulating cell growth, differentiation, matrix production, embryonic development, and apoptosis – in the adult, they are involved in processes such as tissue repair and modulation of the immune system 4q31.22 "
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    ABSTRACT: The 4q deletion syndrome phenotype consists of growth failure and developmental delay, minor craniofacial dysmorphism, digital anomalies, and cardiac and skeletal defects. We have identified an inversion (inv(1)(q25.2q31.1)) and an interstitial deletion in a boy with developmental delay using array-comparative genomic hybridization. This de novo deletion is located at 4q31.21q31.22 (145,963,820- 147,044,764), its size is 0.9-1.1 Mb, and it contains 7 genes (ABCE1, OTUD4, SMAD1, MMAA, C4orf51, ZNF827, and ANAPC10) as well as 5 retrotransposon-derived pseudogenes. Bioinformatic analysis revealed that while small copy number variations seem to have no impact on the phenotype, larger deletions or duplications in the deleted region are associated with developmental delay. Additionally, we found a higher coverage in transposable element sequences in the 4q31.21q31.22 region compared to that of the expected repeat density when regarding any random genome region. Transposable elements might have contributed to the reshaping of the genome architecture and, most importantly, we identified 3 L1PA family members in the breakpoint regions, suggesting their possible contribution in the mechanism underlying the appearance of this deletion. In conclusion, this is one of the smallest deletions reported associated with developmental delay, and we discuss the possible role of genomic features having an impact on the phenotype. © 2014 S. Karger AG, Basel.
    Cytogenetic and Genome Research 04/2014; 142(4). DOI:10.1159/000361001 · 1.56 Impact Factor
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