15q11.2 proximal microduplication: a case report of variable expression (2023)

¹University of Health Sciences, Tepecik Training and Research Hospital, Department of Pediatric Neurology, Izmir, Turkey

²Katip Celebi Izmir University, Faculty of Medicine, Department of Pediatric Neurology, Izmir, Turkey

³University of Health Sciences, Tepecik Training and Research Hospital, Genetic Diagnostic Center, Izmir, Turkey

*Corresponding author:Gunce Basarir, University of Health Sciences, Tepecik Training and Research Hospital, Department of Pediatric Neurology, 35620, Konak, Izmir, Turkey; Phone: +905054024855; E-mail:[email protected]

ABSTRACT

Four highly conserved, non-imprinted genes (NIPA1, NIPA2, CYFIP1 and TUBGCP5) are located on the proximal 15q in a region between BP1 and BP2 of approximately 500 kb. Here we report the carrier of the 15q11.2 breakpoint microduplication inherited from a father with epilepsy, near-normal neurological development, mild intellectual disability, and speech delay. The father had a normal phenotype, indicating variable expression. Proximal breakpoint region 15q 1-2 copy number variants may not warrant clinical outcome due to phenotypic variability and low penetrance. We believe that a better understanding of the possible molecular, genetic and environmental modifying factors underlying the copy number variants at this susceptibility locus will aid our clinical approach.

ENTRY

The proximal long arm of chromosome 15 (15q) is known to be relatively susceptible to non-allelic homologous recombination of low-copy repeat elements in breakpoint (BP) regions. (Gillentine and Schaaf, 2015) [1]. Of the six BP regions (BP1-BP6) on 15q, the BP1-BP3 region, defined as the critical region of Prader-Willi/Angelman syndrome, mediates deletions resulting in Prader-Willi and Angelman syndromes (PWS/AS) (Chamberlain and Lalande, 2010) [2]. Patients with type I PWS/AS deletions (BP1-BP3) show a more severe neuropsychiatric phenotype compared to patients with type II PWS/AS deletions (BP2-BP3), suggesting that the BP1-BP2 region is critical in neurodevelopmental processes (Butler , Bittel, Kibiryeva, Talebizadeh and Thompson, 2004; Sahoo et al., 2007)[3,4].

The region of approximately 500 kilobases (kb) between BP1 and BP2 contains four highly conserved, untyped genes: NIPA1, NIPA2, CYFIP1 and TUBGCP5 (Chai et al., 2003) [5]. Several reports have linked microdeletions and microduplications of these four genes to behavioral problems, developmental delays, learning disabilities, seizures, and psychiatric problems, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADD/ADHD) (Doornbos et al., 2009; van der Zwaag et al., 2010; Burnside et al., 2011; von der Lippe, Rustad, Heimdal, and Rødningen, 2011; Abdelmoity, LePichon, Nyp, Soden, Daniel, and Yu, 2012; Vanlerberghe et al., 2015; Picinelli et al., 2016; Mohan et al., 2019) [6-13]. Recent studies have also shown a more severe phenotype in patients with microdeletions than in patients with microduplications involving these four genes (Burnside et al., 2011; Benítez-Burraco, Barcos-Martínez, Espejo-Portero, and Jiménez-Romero, 2017). [8.14]. In addition, the diversity of phenotypes, ranging from those with severe neuropsychiatric symptoms to asymptomatic carriers, suggests variable expression and incomplete penetrance of copy number variants (CNVs) of this highly unstable region (Benítez-Burraco, Barcos-Martínez, Espejo-Portero, and Jiménez-Romero, 2017) [ 14].

In this report, we present the phenotypic characteristics of a patient with a 15q11.2 microduplication involving the NIPA1, NIPA2, CYFIP1 and TUBGCP5 genes.

CLINICAL PRESENTATION

A 9-year-old boy was referred to the pediatric neurology clinic due to generalized tonic-clonic status epilepticus. Magnetic resonance imaging of the brain, interictal electroencephalogram (EEG) and a detailed neurological examination of the patient showed no changes on admission.

The patient was an only child born to healthy parents, not consanguineous at term by caesarean section due to a history of uterine surgery. The perinatal history was normal. The patient had generalized tonic seizures in neonatal and infancy. He was able to sit and walk unaided at 11 and 20 months, respectively. There was also a slight delay in speech as he was able to speak single words at 20 months of age. He had no significant family history of neuropsychiatric problems, epilepsy, or developmental delay. During follow-up, one of the repeated interictal EEG recordings revealed bilateral temporo-occipital epileptic discharges, while the other EEG recordings showed no abnormalities. Nearly normal neurological development with mild intellectual/learning difficulties was also noted at subsequent visits. The patient has been seizure-free for two years while taking the anticonvulsant sodium valproate. She continues regular check-ups in pediatric neurology and child psychiatry clinics.

GENETIC ANALYSIS

Chromosome microarray analysis was performed using the "Affymetrix GeneChip Array 350K" for copy number variants. The patient was found to have a 507 kb duplication of 4 OMIM genes [TUBGCP5 (608147), CYFIP1 (606322), NIPA2 (608146), NIPA1 (608145)] at 15q11.2. Microarray analysis has been reported as arr [hg19] 15q11.2(22.7-23.2)x3. The parent also had an 854 kb duplication in the same region. Microarray analysis was given as arr [hg19] 15q11.2(22.7-23.6)x3. Maternal microorganism analysis was normal.

Picture 1:Visualization of copy number variation in the BP1-BP2 15q11.2 region

DISCUSSION AND CONCLUSION

In this report, we describe the phenotypic characteristics of a patient with a paternally inherited 507 kb microduplication in the 15q11.2 region of BP1-BP2 comprising four non-imprinted genes: NIPA1, NIPA2, CYFIP1 and TUBGCP5. These four genes play different roles in neuronal connectivity and axonal growth (Picinelli et al., 2016) [13]. NIPA1 and NIPA2 encode magnesium transporters in many tissues, including the brain (Goytain, Hines, El-Husseini, & Quamme, 2007; Goytain, Hines, & Quamme, 2008) [15,16]. Mutations in the NIPA1 gene are associated with autosomal dominant hereditary spastic paraplegia (Reed et al., 2005; Goytain, Hines, El-Husseini, & Quamme, 2007) [16,18], while NIPA2 has been described as a susceptibility gene for absence epilepsy in children (Jiang et al., 2012) [18]. CYFIP1 interacts with the fragile X mental retardation protein in neurons, playing a key role in fragile X syndrome and ASD phenotypes (Nowicki et al., 2007) [19]. TUBGCP5, which encodes the cytoskeletal tubulin complex protein, has also been linked to several neurobehavioral disorders (De Wolf, Brison, Devriendt, & Peeters, 2013) [11].

A wide range of phenotypes have been reported in individuals with localized microduplications in the 15q11.2 region of BP1-BP2, including normal phenotypes as well as delayed neurodevelopment, conduct disorder, ADHD, ASD, OCD, schizophrenia, epilepsy, anorexia and mild dysmorphic features (van der Zwaag et al., 2010; Burnside et al., 2011; Abdelmoity, LePichon, Nyp, Soden, Daniel, and Yu, 2012; Kirov et al., 2012; Picinelli et al., 2016; Benítez-Burraco, Barcos-Martínez, Espejo-Portero and Jiménez-Romero, 2017; Chang et al., 2019; Mohan et al., 2019) [8-10, 12-14, 20-22]. Our patient suffered from epilepsy, mild developmental delay and intellectual/learning disability. The patient's father had a normal phenotype, although in our case the microduplication was paternally inherited, confirming the variable expression of CNVs from this region (Benítez-Burraco, Barcos-Martínez, Espejo-Portero, and Jiménez-Romero, 2017) [14] From CNVs in this may not be sufficient to induce the phenotype, secondary changes may be required to obtain the phenotypic characteristics (Burnside et al., 2011) [9].

Mohan et al. (2019), [14] reported phenotypic features including developmental delay, dysmorphic features, ASD and epilepsy/seizures in 159 out of 215 (74%) carriers of the 15q11.2 microduplication. In addition, they observed phenotypic variation and low penetrance in families with 15q11.2 CNV (Mohan et al., 2019) [14]. In another family report (father and 3 male twin brothers) of microduplications in the 15q11.2 BP1-BP2 region, father and fraternal twins were phenotypically normal, while monozygotic twins had behavioral abnormalities, intellectual deficits, and speech delay, suggesting variable penetrance (Benítez -Burraco, Barcos-Martínez, Espejo-Portero and Jiménez Romero, 2017) [15]. A previous study showed that microduplications in the BP1-BP2 region can also affect the microstructure of the white matter of the brain. They found reduced fractional anisotropy in the group of duplicates compared to the control group (Silva et al., 2019) [23]. In addition, previous reports show that microdeletions in 15q11. Epilepsy is known to be a less common phenotype in individuals with the 15q11.2 BP1-BP2 microduplication than in individuals with a microdeletion of this region (Burnside et al., 2011; Mohan et al., 2019) [9,14]. However, our patient had convulsions in the neonatal period and in childhood.

In conclusion, we report a paternally inherited carrier of the 15q11.2 BP1-BP2 microduplication with epilepsy, near-normal neurological development, mild intellectual disability, and speech delay. The father had a normal phenotype, indicating variable expression. Proximal 15q BP1-BP2 CNV may not guarantee clinical outcome due to phenotypic variability and low penetrance. We believe that a better understanding of the possible underlying molecular, genetic and environmental modifiers of CNVs at this susceptibility locus will aid our clinical approach.

REFERENCE

1. Gillentine MA, Schaaf CP. (2015). Human clinical phenotypes of altered CHRNA copy number7. Biochem Pharmacol. 97(4):352-362.
2. Chamberlain SJ, Lalande M. (2010). Neurodevelopmental disorders involving genomic imprinting on human chromosome 15q11-q13. Neurobiol Dis. 39(1):13-20.
3. Butler MG, Bittel DC, Kibiryeva N, Talebizadeh Z, Thompson T. (2004). Behavioral differences between people with Prader-Willi syndrome and type I or type II deletion and maternal disomy. Pediatrics. 113 (3Pt 1): 565-573.
4. Sahoo T, Bacino CA, German JR, Shaw CA, Bird LM, Kimonis V et al. (2007). Identification of novel 15q11q13 deletions in Angelman syndrome by array-CGH: molecular characterization and genotype-phenotype correlations. Eur J Hum Genet. 15(9):943-949.
5. Chai JH, Locke DP, Greally JM, Knoll JH, Ohta T, Dunai J et al. (2003). Identification of four highly conserved genes between the BP1 and BP2 hotspots of the Prader-Willi/Angelman syndrome deletion region that have undergone evolutionary transposition mediated by flanking duplications. Am J Hum Genet. 73(4):898-925.
6. Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, Dijkhuizen T, Bijlsma EK, Gijsbers AC, et al. (2009). Nine patients with a 15q11.2 microdeletion between breakpoints 1 and 2 of the Prader-Willi critical region, possibly related to conduct disorder. Eur J Med Genet. 52(2-3):108-115.
7. van der Zwaag B, Staal WG, Hochstenbach R, Poot M, Spierenburg HA, de Jonge MV et al. (2010). The cosegregated microduplication of chromosome 15q11.2 identifies two risk genes for autism spectrum disorders. Am J Med Genet B Neuropsychiatrist Genet. 153B(4):960-966.
8. Burnside RD, Passion R, Mikhail FM, Carroll AJ, Robin NH, Youngs EL et al. (2011). Proximal 15q11.2 microdeletion/microduplication between BP1 and BP2: a region prone to neurological dysfunction, including developmental and speech delay. Hmm Genet. 130(4):517-528.
9. von der Lippe C, Rustad C, Heimdal K, Rødningen OK. (2011). 15q11.2 microdeletion - seven new patients with developmental delay and/or behavioral problems. Eur J Med Genet. 54(3):357-660.
10. Abdelmoity AT, LePichon JB, Nyp SS, Soden SE, Daniel CA, Yu S. (2012). Proximal 15q11.2 balance disorders associated with various neuropsychiatric disorders and mild dysmorphic features. J Dev Behav Pediatric. 33(7):570-576.
11. DeWolf V, Brison N, Devriendt K, Peeters H. (2013). Genetic counseling for susceptibility loci and neurodevelopmental disorders: del15q11.2 as an example. Am J Med Genet A. 161A(11):2846-2854.
12. Vanlerberghe C, Petit F, Malan V, Vincent-Delorme C, Bouquillon S, Boute O et al. (2015). 15q11.2 microdeletion (BP1-BP2) and developmental delay, behavioral problems, epilepsy and congenital heart disease: a series of 52 patients. Eur J Med Genet. 58(3):140-147.
13. Picinelli C, Lintas C, Piras IS, Gabriele S, Sacco R, Brogna C et al. (2016). Recurrent microdeletions and microduplications of 15q11.2 BP1-BP2 in the etiology of neurodevelopmental disorders. Am J Med Genet B Neuropsychiatrist Genet. 171(8):1088-1098.
14. Mohan KN, Cao Y, Pham J, Cheung SW, Hoffner L, Ou ZZ et al. (2019). Phenotypic association of CNV breakpoint 1-2 (BP1-BP2) region 15q11.2 in a large cohort of samples referred for genetic diagnosis. J Hum Genet. 64(3):253-255.
15. Benitez-Burraco A, Ships-Martinez M, Mirror-Goalie I, Jimenez-Romero S. (2017). Variable penetrance of 15q11.2 BP1-BP2 microduplications in a family with cognitive and language disorders. Mole's team. 8(3):139-147.
16. Goytain A, Hines RM, El-Husseini A, Quamme GA. (2007). NIPA1 (SPG6), the basis of the autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter. J Biol Chem. 282(11):8060-8068.
17. Goytain A, Hines RM, Quamme GA. (2008). Functional characteristics of NIPA2, a selective Mg2+ transporter. Am J Physiol Cell Physiol. 295(4):C944-C953.
18. Reed JA, Wilkinson PA, Patel H, Simpson MA, Chatonnet A, Robay D et al. (2005). A novel NIPA1 mutation associated with pure autosomal dominant hereditary spastic paraplegia. Neurogenetics. 6(2):79-84.
19. Jiang Y, Zhang Y, Zhang P, Sang T, Zhang F, Ji T et al. (2012). NIPA2 located at 15q11.2 is mutated in patients with absence epilepsy during childhood. Hmm Genet. 131(7):1217-1224.
20. Nowicki ST, Tassone F, Ono MY, Ferranti J, Croquette MF, Goodlin-Jones B et al. (2007). Fragilnog X syndrome with the Prader-Williev phenotype. J Dev Behav Pediatric. 28(2):133-1
21. Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D et al. (2012). De novo CNV analysis implicates specific abnormalities of postsynaptic signaling complexes in the pathogenesis of schizophrenia. Mole's Psychiatry. 17(2):142-153.
22. Chang X, Qu H, Liu Y, Glessner J, Hou C, Wang F, Li J, Slet al. (2019). Microduplications at the 15q11.2 BP1-BP2 locus are enriched in patients with anorexia nervosa. J Psychiatr Res. 113:34-38.
23. Silva AI, Ulfarsson MO, Stefansson H, Gustafsson O, Walters GB, Linden DEJ et al. (2019). Reciprocal white matter changes associated with copy number variation in 15q11.2 BP1-BP2: a diffusion tensor imaging study. Biological psychiatry. 85(7):563-572.