Noninvasive prenatal testing suggesting an abnormality in chromosome 15 confirmed to be a case of Prader-Willi syndrome caused by trisomy rescue in the neonatal period.

We report a case of a neonatal diagnosis of Prader-Willi syndrome caused by uniparental disomy. A 34-year-old pregnant woman underwent noninvasive prenatal testing (NIPT) in a hospital that was not certified by the Japanese Association of Medical Sciences. The results of trisomy 13, 18, and 21 were negative; however, a possible abnormality in chromosome 15 was indicated by the Z-score. Genetic counseling was not performed; thus, the woman did not understand the implication of this result. Therefore, she continued with the pregnancy and delivered a boy weighing 1892 g with hypogonadism at 38 weeks and 5 days. The infant was diagnosed with Prader-Willi syndrome caused by uniparental disomy derived from trisomy rescue. The NIPT results may have reflected placental mosaicism, emphasizing the importance of understanding the limitations of NIPT due to the presence of congenital chromosomal abnormalities that cannot be detected by NIPT platforms.

Altered neuronal physiology, development, and function associated with a common chromosome 15 duplication involving CHRNA7.

BACKGROUND: Copy number variants (CNVs) linked to genes involved in nervous system development or function are often associated with neuropsychiatric disease. While CNVs involving deletions generally cause severe and highly penetrant patient phenotypes, CNVs leading to duplications tend instead to exhibit widely variable and less penetrant phenotypic expressivity among affected individuals. CNVs located on chromosome 15q13.3 affecting the alpha-7 nicotinic acetylcholine receptor subunit (CHRNA7) gene contribute to multiple neuropsychiatric disorders with highly variable penetrance. However, the basis of such differential penetrance remains uncharacterized. Here, we generated induced pluripotent stem cell (iPSC) models from first-degree relatives with a 15q13.3 duplication and analyzed their cellular phenotypes to uncover a basis for the dissimilar phenotypic expressivity. RESULTS: The first-degree relatives studied included a boy with autism and emotional dysregulation (the affected proband-AP) and his clinically unaffected mother (UM), with comparison to unrelated control models lacking this duplication. Potential contributors to neuropsychiatric impairment were modeled in iPSC-derived cortical excitatory and inhibitory neurons. The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or unrelated controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and Wnt, axonal guidance, and GABA receptor signaling. The UM model instead exhibited upregulated expression of genes in many of these same pathways, suggesting that molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in this model. However, both AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity. CONCLUSIONS: These data define both diagnosis-associated cellular phenotypes and shared functional anomalies related to CHRNA7 duplication that may contribute to variable phenotypic penetrance in individuals with 15q13.3 duplication. The capacity for pharmacological agents to rescue some neurodevelopmental anomalies associated with diagnosis suggests avenues for intervention for carriers of this duplication and other CNVs that cause related disorders.

Screening for Copy Number Variations of the 15q13.3 Hotspot in CHRNA7 Gene and Expression in Patients with Migraines.

BACKGROUND: a migraine is a neurological disease. Copy number variation (CNV) is a phenomenon in which parts of the genome are repeated. We investigated the effects of the CNV and gene expression at the location 15q13.3 in the Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7) gene, which we believe to be effective in the migraine clinic. METHODS: we evaluated changes in CHRNA7 gene expression levels and CNV of 15q13.3 in patients with migraine (n = 102, with aura, n = 43; without aura, n = 59) according to healthy controls (n = 120) by q-PCR. The data obtained were analyzed against the reference telomerase reverse transcriptase (TERT) gene with the double copy number by standard curve analysis. Copy numbers were graded as a normal copy (2), gain (2>), and loss (<2). RESULTS: we analyzed using the 2-ΔΔCT calculation method. The CHRNA7 gene was significantly downregulated in patients (p < 0.05). The analysis of CNV in the CHRNA7 gene was statistically significant in the patient group, according to healthy controls (p < 0.05). A decreased copy number indicates a dosage loss. However, no significant difference was observed among gain, normal, and loss copy numbers and expression values in patients (p > 0.05). The change in CNV was not associated with the downregulation of the CHRNA7 gene. CONCLUSION: Downregulation of the CHRNA7 gene may contribute to the formation of migraine by inactivation of the alpha-7 nicotinic receptor (α7nAChR). The association of CNV gains and losses with migraines will lead to better understanding of the molecular mechanisms and pathogenesis, to better define the disease, to be used as a treatment target.

Blended phenotype of combination of HERC2 and AP3B2 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15.

Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disability (ID), a distinctive gait pattern, abnormal behaviors, severe impairment in language development, and characteristic facial features. Most cases are caused by the absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Here, we present the first reported case of a 3-year-old boy with an atypical phenotype of Angelman syndrome due to uniparental isodisomy with two recessive homozygous pathogenic variants: in HERC2 and AP3B2. Known phenotypes related to HERC2 and AP3B2 include ID and early infantile epileptic encephalopathy, respectively. The patient had severe global developmental delay and profound ID and showed a happy demeanor, stereotypic laughter, and hand-flapping movements, but also irritability. Craniofacial dysmorphic features, including brachycephaly, strabismus, wide ala nasi, short philtrum, wide open mouth, and slight hypopigmentation were seen. Progressive microcephaly was noted. Magnetic resonance imaging of the brain showed delayed myelination and cerebral atrophy. Trio whole exome sequencing and CGH-SNP array analysis revealed paternal uniparental isodisomy of chromosome 15 and two coexisting recessive diseases resulting from homozygous HERC2 and AP3B2 pathogenic variants. The pathogenic variant in HERC2 was inherited from his heterozygous-carrier father, and the variant in AP3B2 was de novo. We suppose that these unusual features were the combination of the effect of three concomitant disorders.

Hypogonadism in Patients with Prader Willi Syndrome: A Narrative Review.

Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder related to the lack of a functional paternal copy of chromosome 15q11-q13. Several clinical manifestations are reported, such as short stature, cognitive and behavioral disability, temperature instability, hypotonia, hypersomnia, hyperphagia, and multiple endocrine abnormalities, including growth hormone deficiency and hypogonadism. The hypogonadism in PWS is due to central and peripheral mechanisms involving the hypothalamus-pituitary-gonadal axis. The early diagnosis and management of hypogonadism in PWS are both important for physicians in order to reach a better quality of life for these patients. The aim of this study is to summarize and investigate causes and possible therapies for hypogonadism in PWS. Additional studies are further needed to clarify the role of different genes related to hypogonadism and to establish a common and evidence-based therapy.

Human leukocyte antigen association with familial steroid-sensitive nephrotic syndrome.

Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood. Cases with the familial occurrence of SSNS suggest that genetics may play a role in the disease. Human leucocyte antigen (HLA) alleles have been associated with SSNS. We present genetic findings in nine families (44 participants), each with at least two affected siblings. A total of 19 patients were affected with familial SSNS. Six of nine families showed linkage to markers on chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. Interestingly, we also found linkage of disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score Z = 3.02.Conclusion: Our findings confirm the linkage of HLA markers on chromosome 6, which strengthens the association of HLA alleles in SSNS. What is Known: • Human leukocyte antigen (HLA) alleles have been associated with idiopathic steroid-sensitive nephrotic syndrome (SSNS). Only few studies have investigated the association between HLA alleles and familial SSNS. What is New: • We present evidence of linkage of familial SSNS to chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. We also found linkage of the disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score of Z = 3.02 following autosomal recessive inheritance pattern.

Presence of 15p Marker D15Z1 on the Short Arm of Acrocentric Chromosomes is Associated with Aneuploid Offspring in Mexican Couples.

Variation in the location of the 15p region D15Z1 is recognized as a polymorphism in several human populations. We used high-stringency Fluorescence In Situ Hybridization (FISH) to detect D15Z1 in a Mexican cohort. Here, we report the presence of extra D15Z1 sequences on the p-arm of acrocentric chromosomes other than 15 in two groups of Mexican couples, one with healthy offspring (n = 75) and the other with aneuploid offspring (n = 87), mainly trisomy 21. The additional D15Z1 polymorphism was significantly increased in individuals with aneuploid offspring (26.4%), in comparison to individuals with healthy offspring (14%). The most frequent acceptor chromosome of D15Z1 was chromosome 13p, followed by 14p, and finally, 21p. Our results show an overall frequency of 21.6% of this polymorphism in the Mexican population and suggest that its presence might be associated with the mis-segregation of other acrocentric chromosomes and aneuploid offspring. The high frequency of the polymorphism of the D15Z1 sequence on acrocentric chromosomes other than 15 suggests a sequence homogenization of the acrocentric p arms, related to the important function of the centromere and the nucleolar organization region, which flank satellite III DNA.

Three siblings with Prader-Willi syndrome caused by imprinting center microdeletions and review.

Prader-Willi syndrome (PWS) is a complex genetic imprinting disorder characterized by childhood obesity, short stature, hypogonadism/hypogenitalism, hypotonia, cognitive impairment, and behavioral problems. Usually PWS occurs sporadically due to the loss of paternally expressed genes on chromosome 15 with the majority of individuals having the 15q11-q13 region deleted. Examples of familial PWS have been reported but rarely. To date 13 families have been reported with more than one child with PWS and without a 15q11-q13 deletion secondary to a chromosome 15 translocation, inversion, or uniparental maternal disomy 15. Ten of those 13 families were shown to carry microdeletions in the PWS imprinting center. The microdeletions were found to be of paternal origin in nine of the ten cases in which family studies were carried out. Using a variety of techniques, the microdeletions were identified in regions within the complex SNRPN gene locus encompassing the PWS imprinting center. Here, we report the clinical and genetic findings in three adult siblings with PWS caused by a microdeletion in the chromosome 15 imprinting center inherited from an unaffected father that controls the activity of genes in the 15q11-q13 region and summarize the 13 reported cases in the literature.

Small supernumerary marker chromosome 15 and a ring chromosome 15 associated with a 15q26.3 deletion excluding the IGF1R gene.

Array comparative genomic hybridization is essential in the investigation of chromosomal rearrangements associated with epilepsy, intellectual disability, and dysmorphic features. In many cases deletions, duplications, additional marker chromosomes, and ring chromosomes originating from chromosome 15 lead to abnormal phenotypes. We present a child with epilepsy, cardiac symptoms, severely delayed mental and growth development, behavioral disturbances and characteristic dysmorphic features showing a ring chromosome 15 and a small supernumerary marker chromosome. Array CGH detected a 1 Mb deletion of 15q26.3 in a ring chromosome 15 and a 2.6 Mb copy number gain of 15q11.2 corresponding to a small supernumerary marker chromosome involving proximal 15q. Our findings add to previously published results of 15q11q13 duplications and 15q26 terminal deletions. Based on our study we can support the previous reported limited information about the role of SELS, SNRPA1, and PCSK6 genes in the development of the heart morphology. On the other hand, we found that the copy number loss of our patient did not involve the IGF1R gene which is often associated with growth retardation (short stature and decreased weight). We hypothesize that haploinsufficiency of the 15q26 genomic region distal to IGF1R gene might be related to growth disturbance; however, presence of the ring chromosome 15 itself could also be responsible for the growth delay.

Fecundity in an infertile man with r(15) - a challenge to the current paradigm.

Ring chromosome 15 [r(15)] is a rare condition with a mild-to-severe growth failure, mental disabilities, café-au-lait spots, specific facial features, fertility difficulties and other minor dysmorphic stigmata. Of almost 50 affected individuals reported in the literature, none were assessed for the precise breakpoint positioning, which creates uncertainty in defining a specific phenotype for the deleted segment. This study reports for the first time the vertical transmission of r(15) in three consecutive generations of a family, including a subfertile man, his mother and his newborn infant. Array comparative genomic hybridization results revealed a 563 kb deletion of 15q26.3, overlapping the OMIM genes SNRP1, PCSK6 and TM2D3. The hemizygosity was confirmed with real-time quantitative PCR. Regarding haploinsufficiency in 15q26.3, based on phenotypic characteristics of the carriers, the only rational conclusion is that SNRPA1, PCSK6 and TM2D3 are not gene-dosage sensitive and are probably inherited in an autosomal-recessive manner. Given growth deficiency in r(15) carriers, this shows that the growth retardation cannot be attributed entirely to IGF1R. The predominance of female patients with r(15) is the next as yet unanswered question; incomplete penetrance and/or variable expression of gene(s) in different genders may be involved, but further evidence is needed to support this idea.

Assessing the Clinical Utility of SNP Microarray for Prader-Willi Syndrome due to Uniparental Disomy.

Maternal uniparental disomy (UPD) 15 is one of the molecular causes of Prader-Willi syndrome (PWS), a multisystem disorder which presents with neonatal hypotonia and feeding difficulty. Current diagnostic algorithms differ regarding the use of SNP microarray to detect PWS. We retrospectively examined the frequency with which SNP microarray could identify regions of homozygosity (ROH) in patients with PWS. We determined that 7/12 (58%) patients with previously confirmed PWS by methylation analysis and microsatellite-positive UPD studies had ROH (>10 Mb) by SNP microarray. Additional assessment of 5,000 clinical microarrays, performed from 2013 to present, determined that only a single case of ROH for chromosome 15 was not caused by an imprinting disorder or identity by descent. We observed that ROH for chromosome 15 is rarely incidental and strongly associated with hypotonic infants having features of PWS. Although UPD microsatellite studies remain essential to definitively establish the presence of UPD, SNP microarray has important utility in the timely diagnostic algorithm for PWS.

"It wasn't a disaster or anything": Parents' experiences of their child's uncertain chromosomal microarray result.

Chromosomal microarray is an increasingly utilized diagnostic test, particularly in the pediatric setting. However, the clinical significance of copy number variants detected by this technology is not always understood, creating uncertainties in interpreting and communicating results. The aim of this study was to explore parents' experiences of an uncertain microarray result for their child. This research utilized a qualitative approach with a phenomenological methodology. Semi-structured interviews were conducted with nine parents of eight children who received an uncertain microarray result for their child, either a 16p11.2 microdeletion or 15q13.3 microdeletion. Interviews were transcribed verbatim and thematic analysis was used to identify themes within the data. Participants were unprepared for the abnormal test result. They had a complex perception of the extent of their child's condition and a mixed understanding of the clinical relevance of the result, but were accepting of the limitations of medical knowledge, and appeared to have adapted to the result. The test result was empowering for parents in terms of access to medical and educational services; however, they articulated significant unmet support needs. Participants expressed hope for the future, in particular that more information would become available over time. This research has demonstrated that parents of children who have an uncertain microarray result appeared to adapt to uncertainty and limited availability of information and valued honesty and empathic ongoing support from health professionals. Genetic health professionals are well positioned to provide such support and aid patients' and families' adaptation to their situation as well as promote empowerment. © 2016 Wiley Periodicals, Inc.

DFNB16 is a frequent cause of congenital hearing impairment: implementation of STRC mutation analysis in routine diagnostics.

Increasing attention has been directed toward assessing mutational fallout of stereocilin (STRC), the gene underlying DFNB16. A major challenge is due to a closely linked pseudogene with 99.6% coding sequence identity. In 94 GJB2/GJB6-mutation negative individuals with non-syndromic sensorineural hearing loss (NSHL), we identified two homozygous and six heterozygous deletions, encompassing the STRC region by microarray and/or quantitative polymerase chain reaction (qPCR) analysis. To detect smaller mutations, we developed a Sanger sequencing method for pseudogene exclusion. Three heterozygous deletion carriers exhibited hemizygous mutations predicted as negatively impacting the protein. In 30 NSHL individuals without deletion, we detected one with compound heterozygous and two with heterozygous pathogenic mutations. Of 36 total patients undergoing STRC sequencing, two showed the c.3893A>G variant in conjunction with a heterozygous deletion or mutation and three exhibited the variant in a heterozygous state. Although this variant affects a highly conserved amino acid and is predicted as deleterious, comparable minor allele frequencies (MAFs) (around 10%) in NSHL individuals and controls and homozygous variant carriers without NSHL argue against its pathogenicity. Collectively, six (6%) of 94 NSHL individuals were diagnosed with homozygous or compound heterozygous mutations causing DFNB16 and five (5%) as heterozygous mutation carriers. Besides GJB2/GJB6 (DFNB1), STRC is a major contributor to congenital hearing impairment.

Phenotype of a child with Angelman syndrome born to a woman with Prader-Willi syndrome.

This report describes the phenotype, from early childhood to adolescence, of a girl with Angelman syndrome (AS) born following a maternal transmission of a germline paternal 15q11.2-q13 deletion. During early childhood, she showed a typical AS phenotype, such as jerky movements, poor sleep, high voltage electroencephalography pattern, epilepsy, and a severe developmental disability. As she grew older, indications of phenotypical traits similar to Prader-Willi syndrome (PWS) appeared, in particular hyperphagic behavior and a body fat distribution similar to that reported in PWS. She generally showed cheerful AS behavior and had the characteristic outbursts of laughter, but her attitude to other people did not reflect the usual shared enjoyment of interaction seen in children with AS. In unfamiliar surroundings, she withdrew socially, similar to children with PWS, and her insistence on the same, rigid routines was similar to behavior patterns in PWS. The dysmorphic facial features that characterize AS were blurred in adolescence. The specified features that this AS patient had in common with PWS were hardly incidental and, if verified by upcoming case reports of children born to women with a paternal 15q11.2-q13 deletion, they may show new aspects of genetic imprinting.

Recurrent enlarged nuchal translucency: first trimester presentation of a familial 15q26→qter deletion.

A 15q26 terminal chromosomal microdeletion was associated with markedly enlarged 1st trimester nuchal translucency in three of four pregnancies of a couple seen in our prenatal diagnosis unit. Nuchal translucency was normal in the couple's fourth pregnancy, which did not carry the microdeletion. The diagnosis of a 15q26.2→qter microdeletion was first made when the couple's affected daughter displayed significant postnatal growth delay and minor malformations consistent with this contiguous gene syndrome. The microdeletion was confirmed on archived material from the first pregnancy, and identified prospectively on chorionic villi in the third pregnancy. This is the second reported case of familial recurrence of this microdeletion syndrome. As in the other reported family, no deletion or chromosomal rearrangement was identified in either parent, suggesting gonadal mosaicism as a possible cause. First trimester ultrasound findings in 15q26 terminal deletion syndrome have not previously been described. This family illustrates the utility of performing prenatal chromosomal microarray testing in the presence of ultrasound findings of enlarged nuchal translucency or structural abnormalities.

Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings.

INTRODUCTION: Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion (65-75 % of cases), maternal uniparental disomy 15 (20-30 % of cases), and imprinting defect (1-3 %). DNA methylation analysis is the only technique that will diagnose PWS in all three molecular genetic classes and differentiate PWS from Angelman syndrome. Clinical manifestations change with age with hypotonia and a poor suck resulting in failure to thrive during infancy. As the individual ages, other features such as short stature, food seeking with excessive weight gain, developmental delay, cognitive disability and behavioral problems become evident. The phenotype is likely due to hypothalamic dysfunction, which is responsible for hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency. Obesity and its complications are the major causes of morbidity and mortality in PWS. METHODS: An extensive review of the literature was performed and interpreted within the context of clinical practice and frequently asked questions from referring physicians and families to include the current status of the cause and diagnosis of the clinical, genetics and endocrine findings in PWS. CONCLUSIONS: Updated information regarding the early diagnosis and management of individuals with Prader-Willi syndrome is important for all physicians and will be helpful in anticipating and managing or modifying complications associated with this rare obesity-related disorder.

Autism spectrum disorders and hyperactive/impulsive behaviors in Japanese patients with Prader-Willi syndrome: a comparison between maternal uniparental disomy and deletion cases.

This study aims to compare maternal uniparental disomy 15 (mUPD) and a paternal deletion of 15q11-13 (DEL) of Prader-Willi syndrome (PWS) in regard to autism spectrum disorders (ASD). Forty-five Japanese individuals with PWS were recruited from a single recruitment center. The participants consisted of 22 children (aged from 6 to 12) and 23 adolescents (aged from 13 to 19). Six children and seven adolescents were confirmed as having mUPD. Sixteen children and 16 adolescents were confirmed as having DEL. Under blindness to the participants' genotypes, a single psychologist carried out behavioral and psychological assessments, including the Wechsler Intelligence Scales, Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), and ADHD-Rating Scale-IV (ADHD-RS-IV). Two comparisons were made: one between mUPD and DEL children and another between mUPD and DEL adolescents. In children, no significant differences were found between mUPD and DEL participants in terms of autistic (PARS childhood, P = 0.657) and impulsive behaviors (ADHD-RS-IV hyperactive/impulsive, P = 0.275). In adolescents, mUPD patients showed significantly more autistic symptomatology (PARS adolescent, P = 0.027) and significantly more impulsive behavior (ADHD-RS-IV hyperactive/impulsive, P = 0.01) than DEL patients. Our findings about Japanese PWS patients were consistent with previous researches from western countries not focused on Asian patients, indicating that mUPD cases would be more prone to ASD than DEL cases, regardless of ethnoregional differences. In addition, our data suggested that the behavioral difference between mUPD and DEL cases in terms of autistic and impulsive symptoms tend to be unrecognizable in their childhood.

A survey of seizures and current treatments in 15q duplication syndrome.

OBJECTIVE: Seizures are common in individuals with duplications of chromosome 15q11.2-q13 (Dup15q). The goal of this study was to examine the phenotypes and treatments of seizures in Dup15q in a large population. METHODS: A detailed electronic survey was conducted through the Dup15q Alliance containing comprehensive questions regarding seizures and their treatments in Dup15q. RESULTS: There were 95 responses from Dup15q families. For the 83 with idic(15), 63% were reported to have seizures, of which 81% had multiple seizure types and 42% had infantile spasms. Other common seizure types were tonic-clonic, atonic, myoclonic, and focal. Only 3 of 12 individuals with int dup(15) had seizures. Broad spectrum antiepileptic drugs (AEDs) were the most effective medications, but carbamazepine and oxcarbazepine were also effective, although typical benzodiazepines were relatively ineffective. There was a 24% response rate (>90% seizure reduction) to the first AED tried. For those with infantile spasms, adrenocorticotropic hormone (ACTH) was more effective than vigabatrin. SIGNIFICANCE: This is the largest study assessing seizures in Duplication 15q syndrome, but because this was a questionnaire-based study with a low return rate, it is susceptible to bias. Seizures are common in idic(15) and typically difficult to control, often presenting with infantile spasms and progressing to a Lennox-Gastaut-type syndrome. Seizures in those with int dup(15) are less common, with a frequency similar to the general autism population. In addition to broad spectrum AED, medications such as carbamazepine and oxcarbazepine are also relatively effective in controlling seizures in this population, suggesting a possible multifocal etiology, which may also explain the high rate of infantile spasms. Our small sample suggests a relative lack of efficacy of vigabatrin and other γ-aminobutyric acid (GABA)ergic medications, such as typical benzodiazepines, which may be attributable to abnormal GABAergic transmission resulting from the duplication of a cluster of GABAß3 receptor genes in the 15q11.2-13 region.

Relationship between strabismus associated with Angelman syndrome and orbital anomaly.

PURPOSE: To investigate the relationship between the details of strabismus and orbital abnormalities determined by ocular motility tests and orbital imaging examinations in 9 cases with Angelman syndrome (AS). STUDY DESIGN: A retrospective, clinical report. METHODS: The 9 AS cases (mean age at initial visit: 4.6 ± 8.0 years) were confirmed by genetic diagnosis of the chromosome 15q11-13 region. In all cases, axial imaging of the orbit in the transverse plane of the horizontal extraocular muscles was obtained. The opening angle between both lateral walls of the orbit (greater wing of sphenoid) was measured as the biorbital angle, and compared with the 95% confidence interval of the orbital angle in normal children. RESULTS: All cases had exotropia with means of the distance and near of angle 32.2 prism diopters (Δ) ± 9.7Δ and 32.8Δ ± 8.3Δ. The mean of the biorbital angle was 107.7° ± 7.6°, greater than the biorbital angle of 94.3° ± 5.1° previously reported in 129 normal children (P < 0.0001, t-test). Except for one biorbital angle of 93° in the 25-year-old patient, all the biorbital angles in the 8 children were larger than the upper 95% confidence interval in normal children. Astigmatic and hyperopic ametropic amblyopia were detected in 3 cases and 1 case, respectively. CONCLUSIONS: The frequency of exotropia in AS is higher than previously reported, with our results strongly suggesting that the enlarged biorbital angle is related to the pathogenesis of exotropia in AS.

Expanding deep phenotypic spectrum associated with atypical pathogenic structural variations overlapping 15q11-q13 imprinting region.

BACKGROUND: The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader-Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11-q13 duplication syndrome (resulting from the two common forms of duplications-either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region. METHODS: Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11-q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms. RESULTS: This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11-q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11-q13 duplication syndrome. CONCLUSION: Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype-phenotype correlation for patients impacted by variable structural variations within the 15q11-q13 region.