- Research article
- Open Access
- Open Peer Review
Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAEgenes in a family with developmental delay and behavioural problems
- Valeria Capra†1,
- Marisol Mirabelli-Badenier†2,
- Michela Stagnaro†2,
- Andrea Rossi†3,
- Elisa Tassano†5,
- Stefania Gimelli†4 and
- Giorgio Gimelli†5Email author
© Capra et al.; licensee BioMed Central Ltd. 2012
- Received: 21 March 2012
- Accepted: 1 October 2012
- Published: 4 October 2012
Deletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication.
We analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization.
We have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted.
We report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications.
- Familial 17p13.3 duplication syndrome
- PAFAH1B1 and YWHAE genes
The short arm of chromosome 17 is particularly prone to submicroscopic rearrangements due to the presence of high density low copy repeats (LCRs). The proximal region of the short arm harbors a number of syndromes such as CMT1A (Charcot–Marie–Tooth syndrome type 1A), HNPP (hereditary neuropathy with liability to pressure palsies), Smith–Magenis syndrome, and Potocki–Lupski syndrome. It is known that heterozygous 17p13.3 deletions, including PAFAH1B1 (MIM 601545) and YWHAE (MIM 605066) genes, cause two clinically distinct disorders: LSI (isolated lissencephaly) or MDS (Miller-Dieker syndrome), depending on the size of the deletion . Recently, new genomic disorders have been identified in the MDS locus. To date, twenty-two microdeletions [2–6] and sixteen microduplications [5, 7–9] overlapping the MDS critical region have been described in unrelated individuals. All these submicroscopic rearrangements are variable in size and have distinct breakpoints. Bruno et al. proposed to divide 17p13.3 microduplications in two different classes: class I microduplications involving YWHAE but not PAFAH1B1 showing a phenotype characterized by learning difficulties and/or autism with or without other congenital abnormalities; class II microduplications always harboring PAFAH1B1 that may also include the genomic region encompassing the CRK and YWHAE genes, which are associated with developmental delay, psychomotor delay, and associated hypotonia.
Here we report on a 7-year-old boy and his mother presenting a novel class I 17p13.3 microduplication measuring about 329.5 Kb in length and involving only seven genes, including YWHAE, CRK, and BHLHA9.
Cytogenetic, Fluorescence in situ hybridization and array-CGH analyses
Cytogenetic analysis was performed using GTG-banding techniques on metaphase chromosomes obtained by standard procedures from peripheral blood lymphocytes. FISH analyses, according to standard protocols, were carried out using BlueFISH BAC probes (http://www.cambridgebluegnome.com/bluefish) RP11-294J5 and RP11-100F18 mapping to 17p13.3 at the positions chr17:1, 199,461-1,352,559 and chr17:1,314,902-1,514,082 (build 37.1, Feb 2009), respectively. Array-CGH was additionally performed on the proband and other family members using the Agilent Human Genome CGH Microarray Kit G3 400K (Agilent Technologies, Santa Clara, CA, USA) platform, according to the manufacturer’s instructions. This high resolution 60-mer oligonucleotide-based microarray spans coding and non coding genomic sequences with a median spacing of 5.3 kb. Data analysis was performed using the Agilent Genomic Workbench Lite Edition Software 220.127.116.11(2) with the following settings for CGH aberration calling: ADM-2 algorithm (threshold 5) with a moving average of 500 KB and visual inspection of the log2 ratios. DNA sequence information was according to the UCSC Genome Browser (http://genome.ucsc.edu/; GRCh37/hg19, February 2009).
The use of array-CGH analyses for investigation of children with mental retardation has led to the identification of a growing number of new microdeletion and microduplication syndromes, some of which have been clinically well characterised while some other await further delineation.
The proximal short arm of chromosome 17 is particularly prone to cryptic rearrangements for the presence of a high density of low copy repeats. The Miller-Dieker syndrome (MDS) is localized in the more distal region 17p13.3 containing the PAFAH1B1 (encoding LIS1) and YWHAE genes. Recently, novel co-locating microdeletions and microduplications in chromosome 17p13.3 were identified by array-CGH describing new genomic disorders in the MDS locus. Most of these rearrangements are non-recurring and vary in size, from one hundred kilobases to about three megabases. The clinical characterization of both microdeletions and microduplications has been dissected according to the extension and the genes involved in such rearrangements. The main characteristics of 17p13.3 microdeletion are significant postnatal growth retardation, mild to moderate mental retardation, and facial anomalies.
Phenotypic features of patient with 17p13.3. class I microduplication
Bi et al., subject 1
Bi et al., subject 2
Bruno et al., case 9
Bruno et al., case 11
Gestational age (weeks)
Birth weight (g)
Birth length (cm)
Birth head circumference (cm)
Postnatal growth retardation
+ (75th centile)
+ (90th centile)
+ (90-97th centile)
Delay in motor function
Delay in fine motor skills
Mild to moderate global delay
Normal at 2 years
Behavior problems, aggressive tendencies
Behavior problems particularly with food
Autism trait, facial tic
Thick eyebrows, upslanting palpebral fissures
Thick eyebrows, synophrys
Upslanting palpebral fissures, synophrys
Broad, sparse eyebrows
Squared upturned tip of the nose
Squared, overhanging columella
Squared, upturned tip
Thin upper lip
Thin upper lip
Prominent cupid bow
Prominent cupid bow
Short and stubby with low-set thumbs
Large hands, small distal phalanges
Bilateral groove between toe one and two
Hallux valgus, sandal gap, abnormal toe nails
Corpus callosum hypoplasia and mild cerebellar hypoplasia
Thin corpus callosum
However, in the patient’s family history we have to consider that his mother presented antisocial behaviour, bipolar disorder, and alcoholism, but unfortunately she was not available for clinical evaluation or MRI tests. Furthermore, his father was drug addicted and his grandmother was affected by depression. Several environmental problems, intertwining with genetic factors, affect this family. Although genetic and environmental influences may work independently, research is beginning to acknowledge that these factors work in concert to influence the behavioral phenotype, as depression and anxiety . We should therefore consider the 17p13.3 duplication in terms of genetic contribution to a phenotype that, especially in his mother, seems to be due to different components.
In conclusion, our report contributes to a better definition of the minimal critical region for class 1 microduplications including BHLHA9, YWHAE, and CRK. Additional patients will be necessary to further substantiate the significance of 17p13.3 microduplications and to establish a better genotype-phenotype correlation.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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