CLINICAL REPORT

Neurodevelopmental Delays and Macrocephaly in 17p13.1 Microduplication Syndrome Kathryn Anne Mooneyham,1 Kenton R. Holden,2,3 Sara Cathey,3 Alka Dwivedi,3 Barbara R. Dupont,3 and Michael J. Lyons3* 1

College of Medicine, Medical University of South Carolina, Charleston, South Carolina

2

Neurosciences (Neurology) and Pediatrics, Medical University of South Carolina, Charleston, South Carolina Greenwood Genetic Center, Greenwood, South Carolina

3

Manuscript Received: 14 July 2013; Manuscript Accepted: 23 June 2014

Microduplication of chromosome 17p13.1 is a rarely reported chromosome abnormality associated with neurodevelopmental delays. We describe two unrelated patients with overlapping microduplications of chromosome 17p13.1. The first patient is a 2-year-old male who presented with neurodevelopmental delays and macrocephaly. He was found to have a de novo 788 kb copy gain of 17p13.2p13.1 and a de novo 134 kb copy gain of 17p13.1. These duplications include multiple candidate genes, including EFNB3, NLGN2, DLG4, GABARAP, and DULLARD, which may be responsible for neurodevelopmental delays in affected individuals. The second patient is a 29-year-old female with mild intellectual disability and relative macrocephaly. She was found to have a 62.5 kb copy gain of chromosome 17p13.1 that includes the DLG4, GABARAP, and DULLARD genes. The DLG4, GABARAP, and DULLARD genes included in the microduplications of both our patients appear to be candidate genes for neurodevelopmental delays and macrocephaly in individuals with 17p13.1 microduplication syndrome. Ó 2014 Wiley Periodicals, Inc.

Key words: neurodevelopmental delays; macrocephaly; 17p13.1; duplication

INTRODUCTION Microduplications of chromosome 17p13.1 have recently been reported to be associated with neurodevelopmental delays [Belligni et al., 2012; Coutton et al., 2012]. Microdeletions associated with neurodevelopmental delays and microcephaly which overlap the same region of 17p13.1 have previously been reported in 16 patients [Adam et al., 2009; Krepischi-Santos et al., 2009; Schwarzbraun et al., 2009; Komoike et al., 2010; Schluth-Bolard et al., 2010; Shlien et al., 2010; Zeesman et al., 2012; Giordano et al., 2014]. It has been proposed proposed that alteration of a dose-dependent gene may be responsible for the neurodevelopmental delays in individuals with overlapping microdeletions and microduplications of 17p13.1 [Belligni et al., 2012; Coutton et al., 2012]. Suggested candidate genes for neurodevelopmental delays in individuals reported with 17p13.1 microduplications included EFNB3, FXR2, NLGN2, DLG4, GABARAP, and DULLARD [Belligni

Ó 2014 Wiley Periodicals, Inc.

How to Cite this Article: Mooneyham KA, Holden KR, Cathey S, Dwivedi A, Dupont BR, Lyons MJ. 2014. Neurodevelopmental delays and macrocephaly in 17p13.1 microduplication syndrome. Am J Med Genet Part A 164A:2887–2891.

et al., 2012; Coutton et al., 2012]. The common region of overlap between these reports and cases in the Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl resources (DECIPHER) included the DLG4, GABARAP, and DULLARD genes [Coutton et al., 2012]. We present two patients with neurodevelopmental delays and absolute/relative macrocephaly due to chromosome 17p13.1 duplications. The common region of overlap for the duplications identified in our patients includes the DLG4, GABARAP, and DULLARD genes. We propose that duplication of one or more of these genes are likely to be responsible for neurodevelopmental delays and macrocephaly in our patients.

CLINICAL REPORT Patient 1: The patient is a 2-year-old male with neurodevelopmental delays. He is an only child of healthy, unrelated parents. He was born at term via cesarean secondary to fetal distress, complicated by a nuchal cord. He weighed 2.3 kg without any complications following delivery. His parents first became aware of his developmental delays when he was noticed at 6 months to have head lag. 

Correspondence to: Michael J. Lyons, MD, Greenwood Genetic Center–Charleston Office, 3520 West Montague Avenue, Suite 104, North Charleston, SC 29418. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 13 August 2014 DOI 10.1002/ajmg.a.36708

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2888 Since that time, he has made slow, steady progress without significant regression. He sat and crawled at 18 months. He said his first words at 20 months and at 24 months is saying 5–8 words. Feeding and sleeping have been normal for his age. He is receiving early intervention, speech therapy, physical therapy, and occupational therapy. The past medical history is significant for nystagmus but no structural eye abnormalities have been identified. He also has hyperopia and wears glasses. He has seasonal allergies and has been found to be lactose and soy intolerant. At age 24 months, his height was 84 cm (25th centile), weight was 12.4 kg (25–50th centile), and head circumference was 51.8 cm (greater than 97th centile). In addition to macrocephaly, the patient had a high anterior hairline, broad forehead, triangular face, flat occiput, broad nasal tip, full lips, open-mouth expression, and mild micrognathia (no consent was granted for publishing the patient’s photo). He had tight heel cords bilaterally and mild hypotonia. His muscle mass, gait, and deep tendon reflexes were normal. A brain MRI performed due to macrocephaly revealed enlarged extra-axial spaces without significant structural abnormalities. Microarray analysis identified a 134 kilobase (kb) duplication on chromosome 17p13.1 (7,551,664–7,685,368) and a 788 kb duplication on chromosome 17p13.2p13.1 (6,610,939–7,399,323) (Fig. 1). The duplications were confirmed by quantitative polymerase chain reaction (qPCR) testing. Parental testing identified the duplications to be of de novo origin. Patient 2: The second patient is a 29-year-old female with mild intellectual disability. She was born at 38 weeks gestational age via vaginal delivery to a 22-year-old mother. There were no compli-

AMERICAN JOURNAL OF MEDICAL GENETICS PART A cations or exposures during the pregnancy. She had a birth weight of 2.5 kg. There were no complications following delivery. Her early developmental milestones were reportedly delayed but the exact timing is unknown. She has a full scale IQ of 56. She is conversant and admits to aggression and food hoarding. She has a history of attention deficit hyperactivity disorder, explosive personality disorder, hypertension, type 2 diabetes mellitus, dyslipidemia, microalbuminuria, and seizures. Her seizures have been well controlled on valproate and oxcarbazepine. She has not had a seizure since she was three years old. She had a normal electroencephalogram (EEG) when she was 24 years old. The family history is significant for a maternal first cousin with “brain damage” without a known cause and a maternal uncle who is blind with an unspecified “physical disability”. A physical examination revealed a height of 167.2 cm (75th centile), weight of 86.5 kg (50–75th centile), and head circumference of 57 cm (95th centile). She is considered to have relative macrocephaly based on terminology from an internationally recognized group of dysmorphologists which determined that the term relative macrocephaly can be used when the occipitofrontal head circumference centile is greater than the centile for height based on age and gender [Allanson et al., 2009]. She had a high anterior hairline, broad nasal tip, full lips, and mild micrognathia (no consent was granted for publishing the patient’s photo). Her interpupillary measurement was 7 cm (97th centile) and palpebral fissure length was 3 cm. She had upslanted palpebral fissures and right esotropia. Her ears measured 6.4 cm (75–90th centile). Her antihelices were prominent with unfurled helices. Her hand length

FIG. 1. Microarray results showing copy number gain of the short arm of chromosome 17 for Patients 1 and 2. Patient 1 has two copy number gains, an approximately 788 Kb duplication (chr17:6,610,938–7,399,323[hg18]) that harbors 48 genes of which 28 have OMIM entries including DLG4, GABARAP, and DULLARD. A smaller proximal duplication of approximately 133.7 Kb (chr17:7,551,663–7,685,368[hg18]) was also observed in this individual. In Patient 2, an approximately 62.5 Kb duplication was identified that harbors eight genes of which five have OMIM entries (ACADVL, DLG4, DVL2, GABARAP and DULLARD). Affymetrix Genome-wide SNP 6.0 array was analyzed using the Chromosome Analysis Suite (ChAS v1.2). The copy number gains (horizontal blue bars) observed in both patients is shown by the distribution of copy number probes (log 2 ratio), and allele probes (allele difference), depicting the copy number state of that region. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com]

MOONEYHAM ET AL. was 20 cm (97th centile). She had mild ulnar clinodactyly of the 3rd fingers bilaterally. The neurologic exam was nonfocal with normal cranial nerves, gait, coordination, muscle mass, tone, strength, and deep tendon reflexes. Previous genetic testing included normal high-resolution chromosome analysis, multiplex ligation-dependent probe amplification (MLPA) subtelomere analysis, fragile X molecular testing, methylation for Prader–Willi syndrome, and plasma amino acids. Microarray analysis revealed a 62.5 kb duplication of chromosome 17p13.1 (7,034,796–7,097,308) (Fig. 1). The duplication was confirmed to be a tandem duplication by fluorescence in situ hybridization (FISH) studies. Also, quantitative polymerase chain reaction (qPCR) assay was used to confirm the 17p13.1 duplication. Parental studies were not able to be completed to determine if the duplication was inherited.

DISCUSSION Microduplications of chromosome 17p13.1 have only recently been reported [Belligni et al., 2012; Coutton et al., 2012]. The first report of a 17p13.1 microduplication was a 15-year-old male with moderate intellectual disability and seizures. He had a height at the 25th centile and an occipital frontal circumference at the 75th centile. His growth parameters are consistent with relative macrocephaly based on terminology from an internationally recognized group of dysmorphologists which determined that the term relative macro-

2889 cephaly can be used when the occipitofrontal head circumference centile is greater than the centile for height based on age and gender [Allanson et al., 2009]. He was found to have a de novo 790–830 kb duplication (7,016,453–7,807,789) of 17p13.1. The authors described the possible importance of the NLGN2, FXR2, and EFNB3 genes in causing the patient’s clinical features. Although not mentioned in the report as candidate genes, the duplication also included the DLG4, GABARAP, and DULLARD genes [Belligni et al., 2012]. The second report of a 17p13.1 microduplication was a 4-year-old male with developmental delay and clinical features of Silver–Russell syndrome, including relative macrocephaly. He was found to have a de novo 140 kb duplication (6,306,154–6,446,433) and a de novo 586 kb duplication (6,690,620–7,276,764) of 17p13.1. The NLGN2, FXR2, and EFNB3 genes were not included in the duplications. The DLG4, GABARAP, and DULLARD genes were believed to be the best candidate genes for neurodevelopmental delays [Coutton et al., 2012]. We report on two patients with neurodevelopmental delays and absolute/relative macrocephaly who were found to have overlapping microduplications of chromosome 17p13.1. Our patients and the two previously reported patients with microduplications of 17p13.1 share a common region of overlap. [Belligni et al., 2012; Coutton et al., 2012]. The 62.5 kb duplication identified in our second patient is the smallest reported 17p13.1 duplication and narrows the region of overlap to include the DLG4, GABARAP, and DULLARD genes (Fig. 2). The DLG4 gene encodes the post-synaptic

FIG. 2. UCSC genome browser was utilized to identify the minimal region of overlap for the chromosome 17p duplications (chr17:7,034,796– 7,097,308[hg18]) identified between our two patients and the previous reports by Coutton et al and Belligni et al. The duplications in Patient 1 (horizontal black bars) and Patient 2 (horizontal black bar), as well as the duplications reported by Coutton et al (horizontal black bars) and Belligni et al (horizontal black bar) are shown (upper panel). The lower part shows the eight genes located within the minimal region of overlap and the five OMIM genes (ACADVL, DLG4, DVL2, GABARAP, and DULLARD). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com]

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AMERICAN JOURNAL OF MEDICAL GENETICS PART A

TABLE I. Clinical Features in Patients with 17p13.1 Duplication Feature Neurodevelopmental Delays Macrocephaly Triangular face High anterior hairline Broad nasal tip Micrognathia Full lips Clinodactyly

Patient 1

Patient 2

Belligni et al. [2012]

Coutton et al. [2012]

þ A þ þ þ þ þ 

þ R  þ þ þ þ þ

þ R   þ þ  þ

þ R þ þ  þ  

A, absolute; R, relative; þ, present; , absent.

density protein 95 (PSD95) which plays a role in the control of postsynaptic NMDA receptors [Cheng et al., 2010]. PSD95 is inhibited during early neuronal development and may negatively affect immature neurons if over-expressed [Zheng et al., 2012]. The GABARAP gene is also important in neuronal development and knockdown of the GABARAP homolog in zebrafish results in microcephaly [Komoike et al., 2010]. Knockdown of the homolog of the DULLARD gene in Xenopus results in neural tube defects and microcephaly [Satow et al., 2002]. Due to their role in neural development, we believe the DLG4, GABARAP, and DULLARD genes are potentially related to neurodevelopmental delays and absolute/relative macrocephaly in 17p13.1 microduplications. Our patients and the previously reported patients with microduplications of 17p13.1 have overlapping clinical features including neurodevelopmental delays and absolute/relative macrocephaly (Table I). Neurodevelopmental delays and microcephaly have previously been associated with microdeletions of 17p13.1 [Adam et al., 2009; Krepischi-Santos et al., 2009; Schwarzbraun et al., 2009; Komoike et al., 2010; Schluth-Bolard et al., 2010; Shlien et al., 2010; Zeesman et al., 2012; Giordano et al., 2014]. Microcephaly and macrocephaly have been reported in individuals with reciprocal microdeletions and microduplications, respectively. Bruntetti-Pierri et al. [2008] described 21 individuals with 1q21.1 microdeletion associated with microcephaly and 15 individuals with 1q21.1 microduplication associated with macrocephaly. Shinawi et al. [2010] reported 16p11.2 microdeletions or microduplications in 27 individuals. Macrocephaly was associated with 16p11.2 microdeletion while microcephaly was associated with 16p11.2 microduplication. Low-copy repeats (LCRs) have been identified in the 1q21.1 and 16p11.2 regions and are felt to potentially cause recurrent rearrangements through non-allelic homologous recombination [Bruntetti-Pierri et al., 2008; Shinawi et al., 2010]. It is unclear if LCRs are playing a role with microduplications and microdeletions in the 17p13.1 region as the reported microduplications and microdeletions do not appear to be recurrent [Bruntetti-Pierri et al., 2008; Shinawi et al., 2010; Zeesman et al., 2012]. Dosage sensitive genes in the 1q21.1 and 16p11.2 regions have been proposed to explain the differences in head size [Bruntetti-Pierri et al., 2008; Shinawi et al., 2010]. We

report another potential example of copy number variants involving dosage sensitive genes playing an important role in neural development and brain growth/head size. In conclusion, we report two patients with overlapping 17p13.1 microduplications that include the DULLARD, DLG4, and GABARAP, providing further evidence that copy number variants involving these candidate genes may be responsible for neurodevelopmental delays. Patients with a 17p13.1 microduplication appear to more commonly have absolute/relative macrocephaly while patients with the reciprocal 17p13.1 microdeletion present with microcephaly. We propose that microduplication of 17p13.1 is associated with neurodevelopmental delays and absolute/relative macrocephaly. Furthermore, the 17p13.1 region appears to be another possible example of a reciprocal microdeletion/microduplication syndrome associated with phenotypic difference in head size.

ACKNOWLEDGMENS We would like to thank the patients and their families for their participation.

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Neurodevelopmental delays and macrocephaly in 17p13.1 microduplication syndrome.

Microduplication of chromosome 17p13.1 is a rarely reported chromosome abnormality associated with neurodevelopmental delays. We describe two unrelate...
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