This retrospective study analyzed ultrasound findings, single nucleotide polymorphism microarray (SNP array) results, pregnancy outcomes, and postnatal follow-up data in fetuses with 15q13.3 deletions or duplications. Six fetuses were diagnosed with 15q13.3 deletions and nine with 15q13.3 duplications via SNP array at the prenatal diagnosis center of a single tertiary medical center from August 2017 to December 2024. Maternal demographics, ultrasound findings, SNP array results, pregnancy outcomes, and follow-up information were comprehensively reviewed and analyzed. The deletions sizes in the six deletions ranged from 744 Kb to 1.87 Mb, primarily involving genes such as MTMR15, MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7. The overlapping region was located between 31.9 Mb and 32.5 Mb. In the nine duplication cases, the fragment sizes ranged from 419 Kb to 2.13 Mb, with overlapping region located between 31.9 Mb and 32.4 Mb. Among the six cases of fetal deletions, three (50.0%, 3/6) exhibited ultrasound abnormalities. The observed ultrasound phenotypes primarily consisted of cardiovascular malformations, lateral ventriculomegaly, intrauterine growth retardation, cleft lip and palate, abnormal finger development, and polyhydramnios. In the nine cases with fetal duplications, four (44.4%, 4/9) showed ultrasound abnormalities, predominantly featuring cardiovascular malformations, corpus callosum hypoplasia, enlarged gallbladder, lateral ventriculomegaly, and increased nuchal translucency. Among the six deletions cases, parental origin testing was conducted for five cases, two were identified as maternally inherited and three were de novo. In the nine duplications cases, eight underwent parental origin testing, with five being inherited (three paternal and two maternal) and two were de novo. Follow-up assessments revealed that the Case 7 showed speech and motor developmental delays. Case 8 experienced seizure at four years of age. At 18 months, Case 13 was diagnosed with bilateral strabismus. This study conducted a preliminary assessment of the genotype and phenotype of fetuses with 15q13.3 deletions/duplications, expanding the phenotypic spectrum of this syndrome. The study suggests that prenatal 15q13.3 deletions and duplications may be associated with cardiac malformations and lateral ventriculomegaly, but lack phenotype specificity. Moreover, it is essential to closely monitor the neuropsychiatric development postnatally in fetuses with 15q13.3 deletions and duplications that exhibit normal phenotypes during the prenatal period.

The strongest known genetic risk factor for generalized epilepsy is the human hemizygous 15q13.3 microdeletion (MD). This 1.5 Mb MD encompasses six genes, including CHRNA7 encoding the alpha7 subunit that forms the homo-pentameric nicotinic acetylcholine receptor, a known regulator of the immune system. In the CNS, hyper activation of neuroimmune responses contributes to increased seizure susceptibility. In a mouse model with a hemizygous deletion of the orthologous region (Df(h15q13)/+) (Het), we previously demonstrated increased hippocampal expression of inflammatory cytokines compared to wildtype (WT) mice following a mild peripheral immune challenge. To further characterize neuroimmune responses, hippocampal mRNA expression of the chemokines CXCL2 and CXCL10, and the Gap junction protein connexin 43 (GJA1), all of which are implicated in neuronal hyperexcitability, were determined along with additional immune related targets. Three hours after a lipopolysaccharide (LPS, 0.1 mg/kg) or polyinosinic:polycytidylic acid (Poly(I:C), 5 mg/kg) injection (i.p.), hippocampi were collected, mRNA extracted, and cDNA prepared for qPCR. The results demonstrate extensive upregulation of CXCL2 and CXCL10 expression by LPS and Poly(I:C) (up to 200-fold CXCL2, up to 600-fold CXCL10) (p < 0.0001) with genotype x treatment interactions for CXCL2 by LPS (p < 0.007). Responses to treatment were far smaller in magnitude for all other targets. LPS and Poly(I:C) induced statistically similar increases for Toll-like receptor (TLR)2, TLR4, HMGB1, and C3, but Poly(I:C) had stronger effects on GJA1, TLR3, C1qA and MARCO expression. Remarkably, TLR3 was the only target with significant downregulation of expression after Poly(I:C) (p < 0.0001). In addition, genotype x treatment interactions were detected for TLR3, TLR4, HMGB1, and C1qA (p < 0.02). Thus, a peripheral immune challenge caused extensive increases for CXCL2 and CXCL10, and the genotype-treatment interactions that was seen for several targets, underscored the augmented neuroinflammatory response in mice carrying the MD. Of note is the dramatic upregulation of CXCL10 by low dose Poly(I:C). CXCL10 causes hyperexcitability via neuronal CXCR3 activation. Thus, even an asymptomatic viral infection may increase seizure susceptibility. In summary, a peripheral immune challenge causes strong upregulation of hippocampal inflammatory mediators implicated in neuronal excitability which is particularly detrimental for individuals with high seizure susceptibility, such as carriers of the 15q13.3 MD.

A case of prenatal diagnosis of familial 15q13.2q13.3 microdeletion is presented. A 35-year-old, gravida 2, para 1, woman was referred for genetic counseling because of 15q13.2q13.3 microdeletion in the fetus and the mother. The carrier mother was asymptomatic and normal in phenotype. The woman underwent amniocentesis at 17 weeks of gestation because of short nasal bone on fetal ultrasound. Amniocentesis revealed a karyotype of 46,XX. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr [GRCh37] 15q13.2q13.3 (30,954,726-32,509,926) × 1 with a 1.56-Mb 15q13.2q13.3 microdeletion encompassing six OMIM genes of FAN1, TRPM1, MIR211, KLF13, OTUD7A and CHRNA7. Prenatal ultrasound was normal. The woman had a 4-year-old healthy daughter. Four years ago, during her first pregnancy, she underwent expanded non-invasive prenatal testing (NIPT) in the first trimester, and the result was 15q13.2q13.3 deletion. Subsequent amniocentesis revealed a karyotype of 46,XX, and aCGH analysis on uncultured amniocytes revealed no genomic imbalance. However, no further genetic test in the woman and her husband had been made. Therefore, the woman was not aware of her carrier status when she was pregnant again. During this pregnancy, subsequent aCGH analysis on the parental bloods revealed a 1.56-Mb 15q13.2q13.3 microdeletion in the mother and no genomic imbalance in the father. The woman was hesitant to keep the baby. However, following the genetic counseling, the woman's parents were advised to receive genetic testing for 15q13.2q13.3 microdeletion. The 68-year-old asymptomatic healthy grandfather carried the same 15q13.2q13.3 microdeletion, and the grandmother did not have such a microdeletion. The woman finally decided to continue the pregnancy, and a healthy 2750-g baby was delivered at term with no phenotypic abnormalities. Familial 15q13.2q13.3 microdeletion may present no phenotypic abnormalities in three generations.

Schizophrenia is a neuropsychiatric disorder characterized by various symptoms such as hallucinations, delusions, and disordered thinking. The etiology of this disease is unknown; however, it has been linked to many microdeletion syndromes that are likely to contribute to the pathology of schizophrenia. In this review we have comprehensively analyzed the role of various microdeletion syndromes, like 3q29, 15q13.3, and 22q11.2, which are known to be involved with schizophrenia. A variety of factors lead to schizophrenia phenotypes, but copy number variants that disrupt gene regulation and impair brain function and cognition are one of the causes that have been identified. Multiple case studies have shown that loss of one or more genes in the microdeletion regions lead to brain activity defects. In this article, we present a coherent paradigm that connects copy number variations (CNVs) to numerous neurological and behavioral abnormalities associated with schizophrenia. It would be helpful in understanding the different aspects of the microdeletions and how they contribute in the pathophysiology of schizophrenia.

Copy number variations (CNVs) have been implicated in psychiatric and neurodevelopmental disorders. Especially, 15q13.3 deletions are strongly associated with autism spectrum disorder (ASD), intellectual disability (ID), schizophrenia (SCZ), attention deficithyperactivity disorder (ADHD), and mood disorder. We present two siblings with ASD. They had a father with bipolar disorder (BD). Patient 1 is a 21-year-old female with ASD and mild ID, who had language delay and repetitive behavior in childhood, social difficulties, and refused to go to school because of bullying. She was hospitalized in a psychiatric hospital several times. Patient 2 is a 19-year-old male with ASD and ADHD. He did not have developmental delay, but had social difficulties and impulsiveness, then refused to go to school because of bullying. He was treated by a psychiatrist for anxiety and disrupted sleep rhythms. Array comparative genomic hybridization was performed for the siblings and parents. 15q13.3 deletions were detected in the siblings and their healthy mothers. No other pathogenic CNVs were detected. We performed whole-genome sequencing of the family and identified 13 rare missense variants in brain-expressed genes, which may be responsible for the phenotypic differences between the siblings and their mother. This study shows incomplete penetrance and variable expressivity in 15q13.3 deletions. We detected second-hit variants that may explain the phenotypic differences within this family. In addition, detecting 15q13.3 deletions may lead to early diagnosis and a better prognosis with careful follow-up.