The segregation of different submicroscopic imbalances underlying the clinical variability associated with a familial karyotypically balanced translocation
© Fonseca et al. 2015
Received: 25 September 2015
Accepted: 18 December 2015
Published: 30 December 2015
About 7 % of karyotypically balanced chromosomal rearrangements (BCRs) are associated with congenital anomalies due to gene or regulatory element disruption, and cryptic imbalances on rearranged chromosomes. Rare familial BCRs segregating with clinical features are a powerful source for the identifying of causative genes due to the presence of several affected carriers.
We report on a karyotypically balanced translocation t(2;22)(p13;q12.2) associated with variable learning disabilities, and craniofacial and hand dysmorphisms, detected in six individuals in a three-generation family. Combined a-CGH, FISH and mate-pair sequencing revealed a ten-break complex rearrangement, also involving chromosome 5. As the consequence of the segregation of the derivative chromosomes der(2), der(5) and der(22), different imbalances were present in affected and clinically normal family members, thus contributing to the clinical variability. A 6.64 Mb duplication of a 5q23.2-23.3 segment was the imbalance common to all affected individuals. Although LMNB1, implicated in adult-onset autosomal dominant leukodystrophy (ADLD) when overexpressed, was among the 18 duplicated genes, none of the adult carriers manifested ADLD, and LMNB1 overexpression was not detected in the two tested individuals, after qRT-PCR. The ectopic location of the extra copy of the LMBN1 gene on chromosome 22 might have negatively impacted its expression. In addition, two individuals presenting with more severe learning disabilities carried a 1.42 Mb 2p14 microdeletion, with three genes (CEP68, RAB1A and ACTR2),which are candidates for the intellectual impairment observed in the previously described 2p14p15 microdeletion syndrome, mapping to the minimal overlapping deleted segment. A 5p15.1 deletion, encompassing 1.47 Mb, also detected in the family, did not segregate with the clinical phenotype.
The disclosing of the complexity of an apparently simple two-break familial rearrangement illustrates the importance of reconstructing the precise structure of derivative chromosomes for establishing genotype-phenotype correlations.
About 7 % of karyotypically balanced chromosomal rearrangements (BCR) are associated with congenital anomalies . Truncation of dosage sensitive genes [2, 3] or regulatory genomic landscapes , and cryptic imbalances on the rearranged chromosomes  are often the underlying pathogenic mechanisms in disease-associated BCRs. Rare familial BCRs segregating with clinical features contribute to the identification of causative genes due to the presence of several affected carriers [6, 7]. We describe a three–generation Brazilian family with six individuals carrying a karyotypically balanced chromosomal translocation t(2;22)(p13;q12.2) associated with variable learning disability and craniofacial and hand dysmorphisms. By array-comparative genomic hybridization (a-CGH), fluorescent in situ hybridization (FISH), and mate-pair sequencing (MPS), we demonstrated that the apparently simple two-way balanced translocation was a more complex three-chromosome rearrangement, also involving chromosome 5, with three novel copy number variations: two microdeletions at 2p14 and 5p15, and a microduplication at 5q23.2-23.3. As a consequence of the segregation of the derivative chromosomes 2, 5 and 22, different imbalances were present in affected and clinically normal family members, thus contributing to the clinical variability.
The older brother of the proband (III-3) was delivered at term, also after cesarean section. Birth weight was 3,250 g (25th-50th percentiles). He walked independently at 14 months. At eight years, he was referred to our Genetic Counseling Service due to severe learning difficulties; he could not read. His height was 135 cm (90th percentile) and weight was 33 kg (90th - 97th percentile). He had similar craniofacial dysmorphisms as his brother: turricephaly, flattened facies, high forehead, synophrys, epicanthal folds, low nasal bridge, high-arched palate, and low set ears; his inner and outer intercanthal distances were 30 mm (50th - 75th percentiles) and 82 mm (75th - 90th percentiles), respectively. The hand abnormalities included brachydactyly, cutaneous syndactyly, and clinodactyly of the 5th finger. At the age of 17 years, height was 174 cm (between the 25th and 50th percentiles) and weight was 71.2 kg (between the 50th and 75th percentiles). Severe learning difficulties persisted.
The mother of the boys (II-4) was evaluated at 32 years of age. Her height was 155 cm (10th - 25th percentiles) and her weight was 73 kg (90th - 97th percentiles). She presented with turricephaly, mid facial hypoplasia, low set ears, and bilateral brachydactyly and clinodactyly of the 5th finger. She had learning difficulties. A younger brother of the proband (III-5) was clinically normal.
The maternal grandmother I-2 (deceased from heart failure at the age of 77 years), an uncle (II-6) and an aunt of the proband (II-3), all carriers of the translocation, presented with similar dysmorphisms and variable degrees of learning disabilities; the uncle was more severely affected. These three patients were not personally examined but their clinical conditions were assessed through photos and familial anamnesis.
Chromosome analysis (GTG-banding and FISH)
GTG-banding analysis was performed on metaphases from cultured peripheral blood lymphocytes.
Fluorescent in situ hybridization (FISH)
FISH was performed with BACs and PACs (Additional file 1: Tables S1 and Additional file 2: Table S2) selected on the University of California – Santa Cruz – Genome Browser (UCSC; http://genome.ucsc.edu; hg 19), as previously described .
Array-comparative genomic hybridization (a-CGH)
a-CGH was performed using the Agilent Human Genome 105 K CGH Microarray (Agilent Technologies Inc., Santa Clara, CA, USA). The Agilent Human Genome 60 k CGH Microarray (Agilent Technologies Inc., Santa Clara, CA, USA), was used for patient III-3 and III-6. The microarray chip was scanned on an Agilent Microarray Scanner. Data were processed by Agilent Feature Extraction software 9.5 and analyzed with Agilent CGH Analytics 3.4 Software with the statistical algorithm ADM-2, and sensitivity threshold 6.7. At least three consecutive oligonucleotides had to have aberrant log2 ratios to be called by the software.
Mate-pair sequencing (MPS) library preparation and data analysis
Mate-pair library was prepared for the genomic DNA of the proband (III-4) using the Nextera Mate Pair Sample Preparation kit (Illumina, San Diego, CA, USA). Mate-pair libraries were sequenced on HiSeq2000 (Illumina), as paired-end 100 bp reads (2 × 100 bp). After adapter trimming, reads passing Illumina Chastity filtering (>0.6) were aligned to the human reference genome (hg19), using Burrows-Wheeler Aligner (BWA) . Sequences with more than two mismatches were excluded, together with duplicated sequences corresponding to PCR amplification. Reads not aligning uniquely were discarded from further analysis. Paired-reads aligning to different chromosomes, with unexpected strand orientation or increase/decrease in insert size, were extracted for further analysis. These “discordant” paired-reads were analysed by SVDetect  to predict structural variants (SV). The MPS results were visualized on the Integrative Genomics Viewer . To identify sample-specific structural variants, the predicted SVs were compared with in-house mate-pair data sets, and SVs, which were not unique to the cases, were excluded. Only SVs supported by at least six independent pairs of reads were considered. The analysis focused on chromosomes 2, 5 and 22. Data from FISH and microarray analysis were used as guidelines to interpret the MPS data and to identify “missed” paired-reads necessary to delineate the derivative chromosomes.
Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR)
To evaluate the expression of LMNB1, MARCH3 and FBN2 genes mapping within the detected duplication at 5q23.2-23.3, qRT-PCR analysis was performed. Total RNA was extracted from peripheral blood leucocytes from the proband, his mother and two unrelated healthy controls (aged 25 to 30 year), using the NucleoSpin® RNA II kit (Macherey-Nagel, Düren, Germany). SuperScript III First-strand Synthesis (Invitrogen, California, USA) kit was used for preparing the cDNA. Primers for qRT-PCR were designed for one amplicon of the LMNB1 (lamin B1), MARCH3 (membrane-associated ring finger (C3HC4) 3, E3 ubiquitin protein ligase) and FBN2 (fibrillin 2) cDNAs, using Primer 3 (Additional file 3: Table S3). The amplicons were normalized to the ACTB (actin, beta) gene. qRT-PCR reactions were carried out on an ABI 7500 real-time PCR machine, using the SYBR® green PCR master mix (Applied Biosystems). All samples were tested in triplicate. To calculate the relative and normalized levels of LMNB1, MARCH3 and FBN2 the data was analyzed using Excel (Microsoft Corporation, Redmond, WA) and an unpaired student's t test was performed for statistical analysis.
Investigation of the translocation t(2;22) using a-CGH, FISH, and MPS
Breakpoints (BPs) involved in the t(2;5;22), mapped by FISH, a-CGH and MPS, and truncated genes
BPs mapped by FISH
BPs mapped by a-CGH
BPs mapped by MPS
130,432,974 – 130,476,355
LMNB1, MARCH3 and FBN2 expression analysis
Although LMNB1 is located in the 5q23.2-23.3 duplicated segment, transcript levels were normal in peripheral blood cells from the proband, and decreased in his mother, as demonstrated by qRT-PCR (Additional file 9: Figure S5). In contrast, increased expression of MARCH3 and FBN2 transcripts was detected in the proband and his mother, in accordance with their mapping within the 5q23.2-23.3 duplicated segment (Additional file 9: Figure S5). The decreased levels of LMNB1 transcripts in the mother of the proband in comparison to her son might be due to an age-related effect .
We studied a karyotypically balanced translocation segregating in a family in association with learning disabilities of variable degrees and craniofacial and hand dysmorphisms. By combining a-CGH, FISH and MPS, the rearrangement, first identified by G-banding as a two-way balanced translocation, was found to be a ten-break rearrangement, resulting in six structural variations, which also involved chromosome 5 (Fig. 1a). This rearrangement presumptively originated in an ancestor of the proband’s grandmother, since she did not carry the der(5) with a deletion of the segment corresponding to the 5q23.2-23.3 fragment inserted into der(22); a meiotic exchange between the normal chromosome 5 and the original der(5) would have given rise to the detected der(5) with a normal long arm and an insertion of the 2p14 segment into the short arm (Additional file 8: Figure S4).
Despite the presence of three rearranged chromosomes – der(2), der(5) and der(22), only the der(2) and der(22) chromosomes segregated with clinical features (Fig. 1b). Common to all affected individuals were the 6.64 Mb duplication at 5q23.2-23.3, together with disruption of SLC1A4 and MEIS1-AS3, on chromosome 2, and disruption of TTC28, on chromosome 22. The 1.47 Mb deletion at 5p15, which is a novel copy number variation (CNV) not reported in the Database of Genomic Variants (DGV), did not segregate with the clinical phenotype since the clinically normal brother of the proband (III-5) carried this deletion. He also carried another CNV not reported in DGV, a 1.42 Mb 2p14 duplication; his brother (III-3) and uncle (II-6) carried a deletion of this same fragment. Although this deletion might cause cognitive impairment, as discussed below, duplications of CEP68, RAB1A, ACTR2 and SPRED2, located within the duplicated segment, have not been reported before. The microimbalances detected in the proband’s normal brother (III-5) highlight the importance of investigating unaffected individuals in the evaluation of the clinical impact of familial rearrangements.
There are some reports of larger 5q duplications, which include the present 6.64 Mb 5q23.2-23.3 duplicated segment . However, these previously reported duplications varied in size, the smallest being 14 Mb, and differed in gene content, thus making phenotype-genotype correlations difficult to infer. Among the 18 genes encompassed by the 5q23.2-23.3 duplication in the present family, LMNB1 is the only gene known to cause disease due to increased expression. LMNB1 duplications cause adult-onset autosomal dominant leukodystrophy (ADLD; MIM 169500) . Three other disease genes maps within the 6.64 Mb 5q23.2-23.3 duplicated segment: FBN2 (congenital contractural arachnodactyly), ALDH7A (pyridoxine-dependent form of epilepsy) and MEGF10 (myopathy, areflexia, respiratory distress, and dysphagia). The disorders associated with these genes are caused by gain of function (FBN2) or loss of function mutations (MEGF10 or ALDH7A), and it is unknown if overexpression of these genes is pathogenic. Also, 14 genes, which have not been implicated in diseases before, map within the duplication (PHAX, MARCH3, SLC12A2, SLC27A6, ADAMTS19, CTXN3, CHSY3, ZNF608, GRAMD3, C5orf48, C5orf63, ISOC1, PRRC1, KIAA1024L). Since this novel CNV was detected only in affected family members, duplication of one or more of these 14 genes likely contributes to the phenotype.
ADLD is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system. The first signs of the disease, which includes cerebellar, pyramidal, and autonomic dysfunction, appear in the fourth and fifth decades of life . None of the adults in the family described here, presently in the fourth and fifth decades of life [the proband's mother (aged 46 years), aunt (aged 53 years) and uncle (aged 45 years)], and the grandmother, deceased at the age of 77 years due to heart failure, showed symptoms of this disease. As determined by qRT-PCR, the LMNB1 gene was not overexpressed in blood cells from the proband or his mother (Additional file 9: Figure S5). Increased LMNB1 transcript level is detected not only in brain but also in blood from individuals affected by ADLD [16, 17]. On the other hand, in the proband and his mother, FBN2 and MARCH3 had a 2 to 3.8 fold increase in expression, demonstrating that the extra copy of both genes inserted into the der(22) were functional; these findings indicated that the normal and decreased expression of LMNB1 in the proband and his mother, respectively, did not result from the silencing of the entire 5q23.2-23.3 segment on the der(22) due to “position effect”. Previously reported duplications including LMNB1 in ADLD patients ranged in size from 128 kb to 478 kb; common to all these patients was a duplicated ~72 kb segment (chr5:126,102,443-126,174,517), encompassing the entire coding sequence of LMNB1, and the regions 9.8 kb upstream and 1.8 kb downstream the gene . This interval was duplicated in the present family. Furthermore, a recently isolated LMNB1 enhancer located 120 kb upstream of LMNB1  was also translocated to the der(22). However, the extra copy of LMBN1 was located on the der(22) chromosome, while all previously reported LMNB1 duplications in patients with ADLD were in tandem [14, 16, 17, 19, 20]. The disruption of LMNB1 long range regulation or the interference of sequences on chromosome 22 (centromeric to LMNB1) or from the translocated chromosome 2 (telomeric to LMNB1) might have negatively impacted the expression of the LMNB1 copy located on the der(22). Considering the position of the gene within the duplicated segment, disruption of LMNB1 regulation would be due to the separation of an enhancer located more than 2.3 Mb upstream or 4.3 Mb downstream from LMNB1. The possibility also exists that other genes within the 5q23.2-q23.3 segment negatively affects LMNB1 expression. Regardless of the mechanism interfering with LMNB1 expression, this study illustrates the importance of evaluating the quantitative level of transcripts in carriers of duplications encompassing LMNB1, particularly considering that ADLD is a late-onset neurodegenerative disorder.
SLC1A4 is also disrupted in all carriers of the der(2) chromosome in the present family. SLC1A4 encodes a neutral small amino acid transporter, and is ubiquitously expressed , particularly in glial cells, and during brain development . Recently, recessive mutations in SLC1A4 were described in patients presenting with developmental delay, microcephaly and hypomyelination [23–25]. Most patients were homozygous for missense mutations (p.E256K, p.L315fs, and p.R457W) [23, 24], but one of them carried a missense (E256K) and a nonsense (Leu315Hisfs*42) mutations . Mutated proteins were shown to abolish (p.R457W) or markedly reduce (p.E256K) L-serine transport , demonstrating that SLC1A4 loss of function, rather than a gain of function mechanism, caused the clinical features. Heterozygous carriers of the missense and nonsense mutations in SLC1A4 were clinically normal, arguing against a causative role of the SLC1A4 truncation in the present family. The TTC28 gene on chromosome 22 and the MEIS1-AS3 non coding RNA on chromosome 2 were also disrupted by the breakpoints of the rearrangement. TTC28 and MEIS1-AS3 have not been associated with any known diseases and their phenotypic impact on the carriers of the der(2) and der(22) chromosomes remains unknown.
The t(2;5;22) could have also impacted the long range regulation of gene(s) located near the breakpoints. The breakpoint on chromosome 2 that disrupted MEIS-S3 occurred approximately 10 kb from the MEIS1 gene (Meis homeobox 1). SNPs within MEIS1 were associated with the Restless Legs syndrome (RLS), a neurologic sleep/wake disorder [26, 27]. Although there is no evidence that MEIS-S3 disruption affects MEIS1 expression, the centromeric breakpoint on chromosome 2 occurred within the same topological domain as MEISI , and might have altered its long range regulation. Members of the reported family do not present RLS symptoms, but the role of MESI1 in the development of the central nervous system  could implicate MESI1 as candidate for the learning disabilities observed in the family.
Although the six translocation carriers presented with learning disabilities, these were more pronounced in the proband’s affected brother (III-3) and uncle (II-6), who were the only carriers of the 1.42 Mb chromosome 2 deletion. Seven microdeletions, all extending beyond the 1.42 Mb deletion described here, have been previously reported in association with intellectual disability and minor dysmorphic features, pointing to a 2p14p15 microdeletion syndrome [30–32] (Fig. 3d). The 1.42 Mb deletion detected in III-3 and II-6 is the smallest yet to be reported, encompassing SLC1A4, CEP68 (centrosomal protein 68 kDa), RAB1A (RAB1A, member the RAS oncogene family); ACTR2 (ARP2 actin-related protein 2 homolog), and SPRED2 (Sprouty-related, EVH1 domain containing 2). SLC1A4 was disrupted in all six affected family members, but, this variant is likely not pathogenic in the heterozygous state, as discussed above. CEP68, RAB1A and ACTR2, mapping to the minimal overlapping deleted segment appear as candidates contributing to intellectual impairment in the 2p14p15 microdeletion syndrome (Fig. 3d). RAB1A and ACTR2 are involved in neuronal differentiation and regulation of axon guidance . CEP68 encodes a centrosomal protein; CEP proteins have an important role in neurogenesis in the developing human brain, as demonstrated by the clinical effect of homozygosity for recessive mutations in CEP genes, known to cause primary microcephaly . However, while III-3 and II-6 had severe learning difficulties, the other seven patients with 2p14p15 microdeletions presented with intellectual disability [30–32]. This suggests that, in addition to the gene(s) encompassed by the deletion described here, other gene(s) contribute to the intellectual impairment in the 2p14p15 microdeletion syndrome. Most of the 2p14p15 microdeletion patients also present with genitourinary defects [31, 32] a feature associated with the loss of OTX1 (orthodenticle homeobox1) at 2p15 . The absence of genitourinary defects in III-3 and II-6, whose deletion does not include OTX1, is in line with the role of OTX1 in the development of the genitourinary tract.
The challenge to establish genotype-phenotype correlations in carriers of chromosomal rearrangements extends beyond a particular DNA sequence to reach the genomic context . Although several genes have been directly affected by the herein described t(2;5;22), this rearrangement might have impacted the genetic network by altering the physical relationship between chromatin domains, thus contributing to the clinical phenotype.
The disclosing of the complexity and segregation of an apparently simple two-way rearrangement illustrates the importance of reconstructing the precise structure of derivative chromosomes for genotype-phenotype correlations. As the consequence of the segregation of the derivative chromosomes 2, 5 and 22, different imbalances were present in affected and clinically normal family members, thus contributing to the clinical variability. A 1.42 Mb 2p14 microdeletion, associated with more severe learning disabilities, pinpoints CEP68, RAB1A and/or ACTR2 as candidate(s) for the intellectual impairment in the previously described 2p14p15 microdeletion syndrome. The absence of LMNB1 overexpression, despite the presence of an additional copy of the gene, highlights the importance of genomic topology in disease, supporting the indication of evaluating genetic findings in the genomic context.
This study was approved by the Ethic Committee for research involving human subjects at the Biosciences Institute, University of São Paulo (125/2011). Written informed consent was obtained from the patients or parents for publication of clinical data.
This work was funded by FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo (Grants: CEPID-Human Genome and Stem Cell Research Center 2013/08028-1; student fellowships 2011/14293-4 and 2013/01146-9); the Lundbeck Foundation (2013–14290), the UCPH Programme for Interdisciplinary Research (Global Genes, Local Concerns) and The Danish Council for Independent Research - Medical Sciences (4183-00482B). The authors thank Mrs. Maria Raimunda L. S. Pinheiro for technical support.
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