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

2023: Volume 4, Issue 2

DOI: https://doi.org/10.35702/clinres.10011

(Video) 16p11.2: Neurological Findings

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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

(Video) 16p11.2: What We've Learned about Medical Genetics

*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]


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.


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].

(Video) Lecture 7 - B-cell development & somatic recombination

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


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.


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.

(Video) Congenital deformities of the Upper Limb

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


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.


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Is 15q11 2 microdeletion rare? ›

A 15q11. 2 deletion is a very rare genetic variation in which there is a tiny piece of chromosome 15 missing. The deletion is found at a place called q11. 2.

What is 15q11 2 microdeletion syndrome? ›

2 microdeletion refers to a chromosome abnormality in which a tiny piece of genetic material on the long arm of chromosome 15 (at a location designated q11. 2) is missing (deleted). The features of people with a 15q11. 2 microdeletion vary widely.

What is microduplication of chromosome 15q11 2? ›

A 15q11. 2 microduplication is a rare genetic condition caused by the duplication of a small piece of genetic material from one of the body's 46 chromosomes – chromosome 15. For typical development, chromosomes should contain the expected amount of genetic material (DNA).

What is 15q11 2 copy number variation syndrome? ›

The 15q11. 2 BP1-BP2 copy number variant (CNV) is associated with altered brain morphology and risk for atypical development, including increased risk for schizophrenia and learning difficulties for the deletion.

Is microdeletion a disability? ›

Microdeletion is considered to be one of the prenatal causes of intellectual disability.

Are microdeletions serious? ›

The effect a microdeletion has on your baby's health and development depends on its location and size. Some microdeletions can cause intellectual disability, problems with motor skills or miscarriage, while others do no damage at all.

What is the treatment for microdeletion syndrome? ›

Diagnosis of 3q29 microdeletion syndrome may be suspected by symptoms but is confirmed by genetic testing. [12259] Treatment is based on signs and symptoms of each person and may include surgeries to repair any physical abnormalities, speech therapy, behavior therapy and special education.

What happens if you have microdeletion syndrome? ›

5q31. 3 microdeletion syndrome is a condition characterized by severely delayed development of speech and motor skills, such as walking. Beginning in infancy, affected individuals also have weak muscle tone (hypotonia), feeding difficulties, and breathing problems.

Is microdeletion syndrome a rare disease? ›

1 microdeletion syndrome is a rare chromosome disorder. Symptoms may include seizures, moderate to severe learning problems, speech delays, behavior problems, trouble sleeping, and developmental delays (learn to crawl, sit or walk later than other babies).

What are the symptoms of microduplication syndrome? ›

1 microduplication may be prone to develop cysts, swollen and knotted (varicose) veins, or carpal tunnel syndrome, which is characterized by numbness, tingling, and weakness in the hands and fingers.

Is 16p11 2 microduplication syndrome autism? ›

Autism spectrum disorder, which affects communication and social skills, is diagnosed in about one in five people with a 16p11. 2 duplication. Affected individuals also have an increased risk of mental health problems, including schizophrenia, anxiety, and depression.

What disorders are microduplication? ›

3q29 microduplication syndrome (also known as 3q29 duplication syndrome) is a condition that results from the copying (duplication ) of a small piece of chromosome 3 in each cell. The duplication occurs on the long (q) arm of the chromosome at a position designated q29.

How common is 15q11 2 microdeletion? ›

The 15q11. 2 BP1–BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%–1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls.

Which syndrome will result from a 15q deletion inherited from the father? ›

One of the chromosomes that belongs to pair number 15 is different in Prader-Willi syndrome. Around 70% of cases of Prader-Willi syndrome are the result of missing genetic information from the copy of chromosome 15 inherited from the father. This is referred to as "paternal deletion".

Which syndrome will result from a 15q deletion inherited from the mother? ›

The Prader-Willi syndrome genes on chromosome 15 from his mother are silent or imprinted. He then could pass the chromosome 15 from his mother with the mutation to his child and Prader-Willi syndrome would result.

What is the life expectancy of a person with microdeletion? ›

The average life expectancy is up to about 30 years (in Russia, the maximum life expectancy is 25 years), with severe heart defects, kidneys can be no more than one year. In 80% of newborns suffering from it, the cytological basis of this syndrome is a deletion of the short arm of the 4th chromosome.

What is the most common microdeletion syndrome? ›

The 22q11. 2 deletion syndrome is the most common human chromosomal microdeletion syndrome and one of the most common genetic syndromes associated with prenatally detected congenital heart defects (CHDs). It has a wide range of associated clinical findings.

Can microdeletion syndrome be cured? ›

Although there is no cure for DiGeorge syndrome (22q11. 2 deletion syndrome), treatments can usually correct critical problems, such as a heart defect or cleft palate. Other health issues and developmental, mental health or behavioral problems can be addressed or monitored as needed. Treatments and therapy for 22q11.

What percentage of people have microdeletion syndrome? ›

3q29 microdeletion syndrome appears to be very rare. Based on a study from Iceland, the condition has an estimated incidence of 1 in 30,000 to 40,000 people in that population. About 75 affected individuals have been described in the medical literature.

Can microdeletion be inherited? ›

3 microdeletion syndrome is caused by a deletion on the long arm of chromosome 15 that spans at least 7 genes and usually includes the CHRNA7 gene.It can be inherited in an autosomal dominant manner with reduced penetrance, or can occur as a new (de novo) deletion.

What disease does deletion cause? ›

Deletion mutations are actually the cause for a large number of genetic diseases, such as two-thirds of cystic fibrosis cases and the cat cry syndrome, which is so-called because children with this syndrome often have a cry that sounds similar to a cat meowing.

How rare is microdeletion syndrome? ›

3q29 microdeletion syndrome appears to be very rare. Based on a study from Iceland, the condition has an estimated incidence of 1 in 30,000 to 40,000 people in that population. About 75 affected individuals have been described in the medical literature.

Is 22q11 2 deletion syndrome a rare disease? ›

The prevalence of 22q11. 2DS has been estimated to be approximately 1/3000 to 1/6,000 live births. These numbers may well be higher due to the variability of the condition, difficulty in properly diagnosing, and lack of newborn screening.

Which microdeletion syndrome is most common? ›

DiGeorge syndrome is the most frequent microdeletion syndrome with an incidence range from 1:4000 to 1:10000, according to the literature [6-10].

What is the life expectancy of someone with chromosome deletion? ›

One to two percent of children born with this syndrome have a life expectancy of two to three years; however, most individuals reach adulthood and can live a life span into the fifties. Early treatment should be considered for the most severe issues with this condition to prolong life expectancy.


1. CNV Web Series: Understanding Case-Control Data (February 13, 2020)
(ClinGen Resource)
2. MedEClasses Module Prader Willi Genetics
(Dr Anurag Bajpai)
3. Understanding the Brains of People with Dup15q
(Dup15q Alliance)
4. MedEClasses Grand Round Prader Willi Syndrome
(Dr Anurag Bajpai)
5. SAGES Foregut Facebook Livestream - Alternatives to Nissen
(Society of American Gastrointestinal and Endoscopic Surgeons (SAGES))
6. HGS Webinar Dec2020: Genetic Approach to Hypotonia in a Neonate & Child - By Dr. Ratna Dua Puri
(Human Genetics Society)


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