What Can Really Be Considered a Syndrome? An Insight Based on 16p11.2 Microduplication.

What is the definition of Syndrome? Since the beginning of studies in genetics, certain terminologies have been created and used to define groups of diseases or alterations. With the advancement of knowledge and the emergence of new technologies, the use of basic concepts is being done in a mistaken or often confusing way. Because of this, revisiting and readjusting the old terms becomes imminent. Here, we explore these concepts and their use, through a literature compilation of an already well-defined genetic alteration (16q11.2 microduplication). We bring comparisons in clinical and molecular scope of the alteration itself and its diagnostic methods, to improve the report of cases, rescuing terminologies and their applicability nowadays.

Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype.

BACKGROUND: Chromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty. RESULTS: We identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene. CONCLUSION: This report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.

Proximal 4p Deletion Syndrome in an Infant With Multiple Systemic Anomalies.

BACKGROUND: Contiguous gene deletion in the short arm of chromosome 4 is linked to various neurodevelopmental disorders. METHODS: In this study, we conducted peripheral blood chromosome G-banding karyotyping and whole-exome sequencing (WES) on a proband presenting with anal atresia, global developmental delay, lymphocytosis, and other multisystem anomalies. Additionally, chromosome G-banding karyotyping was also carried out on the proband's parents and brother. RESULTS: The 7-month-old proband was found to have a 26.738 Mb 4p15.33-p14 deletion as identified by chromosome G-banding karyotyping and WES. CONCLUSION: We identified a patient with proximal 4p deletion syndrome by karyotype and WES analysis, which might explain some of his phenotypes. Our research enhances clinicians' knowledge of this rare condition, and offers valuable genetic counseling to the affected family. Further research is necessary to identify the causative gene or critical region associated with proximal 4p deletion syndrome.

Unusual Maternal and Fetal Findings With Cell-Free DNA Screening.

Importance: With advances in prenatal cell-free DNA (cfDNA) technology, the information available with cfDNA continues to expand beyond the common fetal aneuploidies such as trisomies 21, 18, and 13. Due to the admixture of maternal and fetal/placental DNA, prenatal cfDNA remains a screening test with the possibility of false-positive and false-negative results. Objective: This review aims to summarize unusual incidental maternal and fetal genomic abnormalities detectable by cfDNA and to provide anticipatory guidance regarding management. Evidence Acquisition: Of 140 articles identified with keywords such as "incidental" and "discordant" cfDNA, 55 original research articles, review articles, case series, and societal guidelines were reviewed. Results: Prenatal cfDNA may incidentally identify a spectrum of maternal genomic abnormalities such as malignancy, mosaicism, and copy number variants. When discordant with fetal diagnosis, these cases require additional investigation with maternal genetic testing and follow-up evaluation. Such incidental fetal/placental abnormalities may include rare autosomal trisomies, uniparental disomy, and triploidy. Further evaluation of fetal/placental abnormalities can be pursued with a combination of ultrasound and prenatal diagnosis with chorionic villous sampling and/or amniocentesis. Societal guidelines do not currently recommend cfDNA screening for rare autosomal trisomies, microdeletions, or copy number variants, and some experts suggest that sex chromosome screening should be opted in after counseling. Conclusions: Knowledge about possible incidental findings with prenatal cfDNA is needed to inform pretest and posttest counseling with appropriate follow-up evaluation. Relevance: As cfDNA technology has advanced to include genome-wide findings, it is important for clinicians, genetic counselors, and societal guidelines to acknowledge the spectrum of possible results outside of the traditional and sex chromosome aneuploidies.

Performance evaluation of noninvasive prenatal testing on 24 chromosomes in a cohort of 118,969 pregnant women in Sichuan, China.

OBJECTIVE: This study aimed to comprehensively analyze the detection capacity of non-invasive prenatal testing (NIPT) for chromosomal abnormalities of all 24 chromosomes, as well as high-risk indications for pregnancy and the fetal fraction, in a large cohort. METHODS: We retrospectively enrolled 118,969 pregnant women who underwent NIPT at Sichuan Provincial Maternity and Child Health Care Hospital from March 2019 to June 2022. The sensitivity, specificity, positive predictive value, negative predictive value, and positive chromosomal abnormality rate were calculated. The fetal fraction based on gestational age, maternal body mass index, and number was examined. RESULTS: NIPT demonstrated > 99% sensitivity and specificity for almost all of the common trisomies (T21, T18, and T13), sex chromosomal aneuploidies, rare autosomal trisomies, and microdeletion/microduplication syndromes. Positive predictive values varied from 12.0% to 89.6%. Advanced maternal age was associated with an increased risk of three major aneuploidies. The fetal fraction was positively correlated with gestational age and negatively correlated with the maternal body mass index. CONCLUSIONS: NIPT can be used to effectively screen for chromosomal abnormalities across all 24 chromosomes. Advanced maternal age is a risk factor for high-risk pregnancy, and careful consideration of the fetal fraction is essential during NIPT.

Genetic counseling of mosaic and non-mosaic tetrasomy 9p at prenatal diagnosis.

Genetic counseling of mosaic and non-mosaic tetrasomy 9p remains difficult because of the possible associated congenital abnormalities, cytogenetic discrepancy in various tissues, true-positive and false-positive diagnosis in non-invasive prenatal testing (NIPT), uniparental disomy (UPD) 9, tissue-limited mosaicism, perinatal progressive decrease of the aneuploid cell line, phenotypic normal carriers and possible favorable fetal outcome in the cases with mosaic tetrasomy 9p at amniocentesis. This article presents a comprehensive review of various counseling issues concerning mosaic and non-mosaic tetrasomy 9p at prenatal diagnosis, and the information provided is very useful for genetic counseling under such circumstances.

[Expert consensus on the clinical application of efficient intelligent chromosomal karyotyping precise auxiliary diagnosis system].

Chromosomal karyotyping analysis has been considered as the gold standard for cytogenetic diagnosis and an effective measure for preventing birth defects. However, conventional karyotyping analysis relies heavily on manual recognition, which is time-consuming and labor-intensive. The application of an efficient intelligent chromosomal karyotyping precise auxiliary diagnosis system in clinical practice can significantly reduce the analysis time and greatly improve the efficiency, increase the detection rate for low-percentage mosaicisms, and promote homogenization between laboratories. This can effectively enhance the capacity and level of cytogenetic diagnosis. With the continuous application of such system in the field of karyotyping analysis, a substantial amount of clinical application data and experience has been accumulated. This consensus has been formulated after multiple rounds of discussion by experts from the clinical application collaboration group of the efficient intelligent chromosomal karyotyping precise auxiliary diagnosis system. It aims to provide a reference for peers to better utilize intelligent auxiliary diagnosis systems during chromosomal karyotyping analysis and promote the standardized development of karyotyping analysis technology.

[Clinical features and genetic analysis of four children with Phelan-McDermid syndrome].

OBJECTIVE: To explore the clinical characteristics and genetic etiology of four children with Phelan-McDermid syndrome (PMS). METHODS: Four children who had visited the Ningbo Women and Children's Hospital between June 2, 2022 and May 8, 2023 were selected as the study subjects. Clinical data of the children were collected. Genomic DNA was extracted from peripheral blood samples of the children and their parents and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and quantitative PCR (q-PCR) analysis. RESULTS: All children had presented with speech and language delays and intellectual disability. Children 3 and 4 also presented with autistic behaviors. WES showed that the children 1 and 2 had respectively carried a heterozygous c.731T>C (p.Leu244Pro) and a c.2782_2851del (p.Gly928ArgfsTer4) variant of the SHANK3 gene. Sanger sequencing confirmed that their parents did not carry the same variant, suggesting that they were de novo in origin. Children 3 and 4 had respectively harbored a 121 Kb and 52.02 Kb heterozygous deletion at chromosome 22q13.33, which had both encompassed the SHANK3 and ACR genes mapped to 22q13.33. q-PCR results showed that the deletion of SHANK3 and ACR genes were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.731T>C and c.2782_2851del variants were predicted to be likely pathogenic (PS2+PM2_Supporting+PP3) and pathogenic (PVS1+PM2_Supporting+PS2_Supporting), respectively. Furthermore, the 52.02 Kb and 121 Kb heterozygous deletions in 22q13.33 were both predicted to be pathogenic (2D+4C, 1.05 in score; 2D+4C, 1 in score). CONCLUSION: The four children were all diagnosed with PMS by genetic testing. Above finding has enriched the phenotypic and mutational spectrum of PMS, and provided a basis for clinical diagnosis and genetic counseling for their families.

Using a new analytic approach for genotyping and phenotyping chromosome 9p deletion syndrome.

Using a new analytic method ("unique non-overlapping region" (UNOR) analysis), we characterized the genotypes and phenotypes of a large cohort of individuals diagnosed with chromosome 9p deletion syndrome (9PMS) and defined critical genomic regions. We extracted phenotypic information from 48 individuals with 9PMS from medical records and used a guided interview with caregivers to clarify ambiguities. Using high-resolution whole-genome sequencing for breakpoint definition, we aligned deletions and drew virtual breakpoints to obtain UNORs associated with phenotypic characteristics. We next extracted genotype and phenotype data for 57 individuals identified from a systematic review of the 9PMS literature and analyzed these as above. Common phenotypic features included developmental delay/intellectual disability, dysmorphic features, hypotonia, genital defects in XY individuals, psychiatric diagnoses, chronic constipation, atopic disease, vision problems, autism spectrum disorder, gastroesophageal reflux disease, trigonocephaly, congenital heart disease, and neonatal hypoglycemia. Our approach confirmed previous literature reports of an association of FREM1 with trigonocephaly and suggested a possible modifier element for this phenotype. In conclusion, the UNOR approach delineated phenotypic characteristics for 9PMS and confirmed the critical role of FREM1 and a possible long-distance regulatory element in pathogenesis of trigonocephaly that will need to be replicated in future studies.

Comparative analysis of the application with the combination of CMA and karyotype in routine and late amniocentesis.

PURPOSE: This is a retrospective comparative study. We aimed to analyze the results of karyotype and chromosomal microarray analysis (CMA) of amniotic fluid across different gestational weeks and evaluate the clinical value in prenatal diagnosis, particularly in the late pregnancies. METHODS: Samples from 580 pregnant women of 18-23 weeks of gestation (mid-gestation group) and 196 pregnant women of 24-32 weeks of gestation (late group) were performed both standard G-band karyotype analysis and CMA. RESULTS: Among the 580 pregnant women in the routine group, the most common indications were positive Down's screening (213/580, 36.7%), followed by advanced maternal age (196/580, 33.8%); while fetal structural anomalies on ultrasonography were the top reason for amniocentesis in the late group (56/196, 28.6%). In the routine group, the total detection rate was 12.1% (70/580), of which 4.1% (24/580) were identified by karyotype analysis and 11.2% (65/580) by CMA. The total detection rate was 15.3% (30/196) in the late group, of which 5.1% (10/196) were detected by karyotype analysis, and 14.3% (28/196) by CMA. CONCLUSION: Karyotype analysis and CMA are complementary in detecting chromosomal abnormalities. Amniotic cavity puncture in the karyotype analysis in 18-23 weeks of gestation and 24-32 weeks of gestation is safe and effective, more obvious effect on the latter.

Prediction of chromosomal abnormalities in the screening of the first trimester of pregnancy using machine learning methods: a study protocol.

BACKGROUND: For women in the first trimester, amniocentesis or chorionic villus sampling is recommended for screening. Machine learning has shown increased accuracy over time and finds numerous applications in enhancing decision-making, patient care, and service quality in nursing and midwifery. This study aims to develop an optimal learning model utilizing machine learning techniques, particularly neural networks, to predict chromosomal abnormalities and evaluate their predictive efficacy. METHODS/ DESIGN: This cross-sectional study will be conducted in midwifery clinics in Mashhad, Iran in 2024. The data will be collected from 350 pregnant women in the high-risk group who underwent screening tests in the first trimester (between 11-14 weeks) of pregnancy. Information collected includes maternal age, BMI, smoking habits, history of trisomy 21 and other chromosomal disorders, CRL and NT levels, PAPP-A and B-HCG levels, presence of insulin-dependent diabetes, and whether the pregnancy resulted from IVF. The study follows up with the women during their clinic visits and tracks the results of amniocentesis. Sampling is based on Convenience Sampling, and data is gathered using a checklist of characteristics and screening/amniocentesis results. After preprocessing, feature extraction is conducted to identify and predict relevant features. The model is trained and evaluated using K-fold cross-validation. DISCUSSION: There is a growing interest in utilizing artificial intelligence methods, like machine learning and deep learning, in nursing and midwifery. This underscores the critical necessity for nurses and midwives to be well-versed in artificial intelligence methods and their healthcare applications. It can be beneficial to develop a machine learning model, specifically focusing on neural networks, for predicting chromosomal abnormalities. ETHICAL CODE: IR.MUMS.NURSE.REC. 1402.134.

Approximately 3% of newborns are affected by congenital abnormalities and genetic diseases, leading to disability and death. Among live births, around 3000 cases of Down syndrome (trisomy 21) can be expected based on the country's birth rate. Pregnant women carrying fetuses with Down syndrome face an increased risk of pregnancy complications. Artificial intelligence methods, such as machine learning and deep learning, are being used in nursing and midwifery to improve decision-making, patient care, and research. Nurses need to actively participate in the development and implementation of AI-based decision support systems. Additionally, nurses and midwives should play a key role in evaluating the effectiveness of artificial intelligence-based technologies in professional practice.

Prenatal diagnosis and genetic analysis of small supernumerary marker chromosomes in the eastern chinese han population: A retrospective study of 36 cases.

BACKGROUND: Small supernumerary marker chromosomes (sSMCs) are additional chromosomes with unclear structures and origins, and their correlations with clinical fetal phenotypes remain incompletely understood, which reduces the accuracy of genetic counseling. METHODS: We conducted a retrospective analysis of a cohort of 36 cases of sSMCs diagnosed in our center. We performed G-banding and chromosomal microarray analysis (CMA). The resulting karyotypes were compared with case reports in the literature and various databases including OMIM, DECIPHER, ClinVar, ClinGen, ISCA, DGV, and PubMed. RESULTS: Karyotype analysis data revealed that 19 out of 36 fetuses were mosaic. Copy number variants (CNVs) analysis results showed that 27 out of 36 fetuses harbored pathogenic/likely pathogenic variants. Among these 27 cases, 11 fetuses carried sex chromosome-related CNVs, including 4 female cases exhibiting Turner syndrome phenotypes and 7 cases showing Y chromosome deletions. In the remaining 16 fetuses with autosomal CNVs, 9 fetuses carried variants associated with Cat eye syndrome, Emanuel syndrome, Tetrasomy 18p, and 15q11-q13 duplication syndrome. Among these, 22 fetuses were terminated, and the remaining 5 fetuses were delivered and developed normally. Additionally, we identified a few variants with unclear pathogenicity. CONCLUSION: Cytogenetic analysis is essential for identifying the pathogenicity of sSMCs and increasing the accuracy of genetic counseling.

Prenatal detection of distal 18p deletion by chromosomal microarray analysis: Three case reports and literature review.

BACKGROUND: Chromosome 18p deletion syndrome is caused by total or partial deletion of the short arm of chromosome 18 and associated with cognitive impairment, growth retardation and mild facial dysmorphism. However, most studies on the genotype-phenotype correlations in the 18p region are diagnosed postnatally. Prenatal reports involving 18p deletions are limited. METHODS: Three pregnant women opted for invasive prenatal testing due to noninvasive prenatal testing indicating high risk for chromosome 18 abnormalities. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed simultaneously. The pregnancy outcomes for all cases were followed up. Meanwhile, we also made a literature review on prenatal phenotypes of 18p deletions. RESULTS: G-banding analysis showed that 2 fetuses presented abnormal karyotypes: 45,XN,der(18)t(18;21)(p11; q11),-21 (case 2) and 46,XN,18p- (case 3). The karyotype of case 1 was normal. Meanwhile, CMA detected 4.37 Mb (case 1), 7.26 Mb (case 2) and 14.97 Mb (case 3) deletions in chromosome 18p region. All 3 pregnancies were terminated finally according to genetic counseling based upon abnormal CMA results. CONCLUSION: Prenatal diagnosis of 18p deletion syndrome is full of challenges due to the phenotypic diversity, incomplete penetrance and lack of prenatal phenotypes. Increased nuchal translucency and holoprosencephaly are common prenatal phenotypes of distal 18p deletion. For fetuses carrying 18p deletions with atypical sonographic phenotypes, noninvasive prenatal testing could be adopted as an effective approach.

Chromosomal abnormalities detected by chromosomal microarray analysis and pregnancy outcomes of 4211 fetuses with high-risk prenatal indications.

With the gradual liberalization of the three-child policy and the development of assisted reproductive technology in China, the number of women with high-risk pregnancies is gradually increasing. In this study, 4211 fetuses who underwent chromosomal microarray analysis (CMA) with high-risk prenatal indications were analysed. The results showed that the overall prenatal detection rate of CMA was 11.4% (480/4211), with detection rates of 5.82% (245/4211) for abnormal chromosome numbers and 5.58% (235/4211) for copy number variants. Additionally, the detection rates of clinically significant copy number variants were 3.78% (159/4211) and 1.8% (76/4211) for variants of uncertain significance. The detection rates of fetal chromosomal abnormalities were 6.42% (30/467) for pregnant women with advanced maternal age (AMA), 6.01% (50/832) for high-risk maternal serum screening (MSS) results, 39.09% (224/573) with abnormal non-invasive prenatal testing (NIPT) results, 9.21% (127/1379) with abnormal ultrasound results, and 5.1% (49/960) for other indications. Follow-up results were available for 4211 patients, including 3677 (3677/4211, 87.32%) whose infants were normal after birth, 462 (462/4211, 10.97%) who terminated their pregnancy, 51 (51/4211, 1.21%) whose infants were abnormal after birth, and 21 (21/4211, 0.50%) who refused follow-up. The results of this study demonstrate significant variation in the diagnostic rate of chromosomal microarray analysis across different indications, providing valuable guidance for clinicians to assess the applicability of CMA technology in prenatal diagnosis.

Prenatal phenotypes and pregnancy outcomes of fetuses with 16p11.2 microdeletion/microduplication.

BACKGROUND: Chromosomal 16p11.2 deletions and duplications are genomic disorders which are characterized by neurobehavioral abnormalities, obesity, congenital abnormalities. However, the prenatal phenotypes associated with 16p11.2 copy number variations (CNVs) have not been well characterized. This study aimed to provide an elaborate summary of intrauterine phenotypic features for these genomic disorders. METHODS: Twenty prenatal amniotic fluid samples diagnosed with 16p11.2 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed in parallel. The pregnancy outcomes and health conditions of all cases after birth were followed up. Meanwhile, we made a pooled analysis of the prenatal phenotypes in the published cases carrying 16p11.2 CNVs. RESULTS: 20 fetuses (20/20,884, 0.10%) with 16p11.2 CNVs were identified: five had 16p11.2 BP2-BP3 deletions, 10 had 16p11.2 BP4-BP5 deletions and five had 16p11.2 BP4-BP5 duplications. Abnormal ultrasound findings were recorded in ten fetuses with 16p11.2 deletions, with various degrees of intrauterine phenotypic features observed. No ultrasound abnormalities were observed in any of the 16p11.2 duplications cases during the pregnancy period. Eleven cases with 16p11.2 deletions terminated their pregnancies. For 16p11.2 duplications, four cases gave birth to healthy neonates except for one case that was lost to follow-up. CONCLUSIONS: Diverse prenatal phenotypes, ranging from normal to abnormal, were observed in cases with 16p11.2 CNVs. For 16p11.2 BP4-BP5 deletions, abnormalities of the vertebral column or ribs and thickened nuchal translucency were the most common structural and non-structural abnormalities, respectively. 16p11.2 BP2-BP3 deletions might be closely associated with fetal growth restriction and single umbilical artery. No characteristic ultrasound findings for 16p11.2 duplications have been observed to date. Given the variable expressivity and incomplete penetrance of 16p11.2 CNVs, long-term follow-up after birth should be conducted for these cases.

Genetic components of microdeletion syndromes and their role in determining schizophrenia traits.

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.

Rock2 heterozygosity improves recognition memory and endothelial function in a mouse model of 16p11.2 deletion autism syndrome.

Rho-associated protein kinase-2 (ROCK2) is a critical player in many cellular processes and was incriminated in cardiovascular and neurological disorders. Recent evidence has shown that non-selective pharmacological blockage of ROCKs ameliorates behavioral alterations in a mouse model of 16p11.2 haploinsufficiency. We had revealed that 16p11.2-deficient mice also display cerebrovascular abnormalities, including endothelial dysfunction. To investigate whether genetic blockage of ROCK2 also exerts beneficial effects on cognition and angiogenesis, we generated mice with both 16p11.2 and Rock2 haploinsufficiency (16p11.2df/+;Rock2+/-). We find that Rock2 heterozygosity on a 16p11.2df/+ background significantly improved recognition memory. Furthermore, brain endothelial cells from 16p11.2df/+;Rock2+/- mice display improved angiogenic capacity compared to cells from 16p11.2df/+ littermates. Overall, this study implicates Rock2 gene as a modulator of 16p11.2-associated alterations, highlighting its potential as a target for treatment of autism spectrum disorders.

18q Deletion Syndrome Presenting with Late-Onset Combined Immunodeficiency.

Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4+ and/or CD8+ cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence.

Cell-free DNA test for fetal chromosomal abnormalities in multiple pregnancies.

INTRODUCTION: This study aimed to report the screening performance of cell-free DNA (cfDNA) testing for chromosomal abnormalities in twins, triplets, and vanishing twin pregnancies. MATERIAL AND METHODS: Data were obtained from pregnant women with a multiple pregnancy or a vanishing twin pregnancy at ≥10 weeks' gestation who requested self-financed cfDNA testing between May 2015 and December 2021. Those that had positive screening results had diagnostic confirmatory procedures after counseling and consent. The performance of screening of the cfDNA test was determined by calculating confirmation rate and combined false-positive rate (cFPR). RESULTS: Data from 292 women were included after exclusion of those lost to follow-up, with no-result on cfDNA testing, or had reductions. Of the 292 pregnancies, 10 (3.4%) were triplets, including no cases of trisomy 21 and trisomy 18; 249 (85.3%) were twins, including 3 cases of trisomy 21 and no cases of trisomy 18 and 13; and 33 (11.3%) were vanishing twins, including 3 cases of trisomy 21 and 1 case of trisomy 18. The median (IQR) maternal age was 34 years (31-37). For triplet pregnancies, the initial no-result rate was 10.3% (95% confidence interval [CI] 3.6-26.4), all with results after redraw. For twin pregnancies, the initial no-result rate was 12.9% (95% CI 9.6-17.0), and the no-result rate after redraw was 1.6% (95% CI 0.7-3.6). For vanishing twins, there were no cases with no-result. All triplets had low-risk cfDNA results. The confirmation rate for trisomy 21 was 100% with a FPR at 0% due to the small number of positive cases for twins. For vanishing twins, one high-risk case for trisomy 21 and the only high-risk case for trisomy 18 were confirmed with a cFPR of 8.3% (n = 2/24; 95% CI 2.3-25.9). CONCLUSIONS: cfDNA testing in twin pregnancies has sufficient screening performance for trisomy 21 but the number of affected cases for other conditions is limited to draw any meaningful conclusion. The use of cfDNA testing in triplet pregnancies and vanishing twins remains an area for further research.

Epilepsy, EEG and chromosomal rearrangements.

Chromosomal abnormalities are associated with a broad spectrum of clinical manifestations, one of the more commonly observed of which is epilepsy. The frequency, severity, and type of epileptic seizures vary according to the macro- and microrearrangements present. Even within a single chromosomal anomaly, we most often deal with a phenotypic spectrum. The aim of the study was to look for chromosomal rearrangements with a characteristic electroencephalographic pattern. Only a few disorders have peculiar electroclinical abnormalities: 1p36, 4p16, 6q terminal or trisomy 12p, Angelman syndrome, inv dup 15, 15q13.3 deletions, ring 20, Down syndrome, or Xp11.22-11.23 duplication. We also reviewed studies on epileptic seizures and typical electroencephalographic patterns described in certain chromosomal rearrangements, focusing on the quest for potential electroclinical biomarkers. The comprehensive review concludes with clinical presentations of the most common micro and macro chromosomal rearrangements, such as 17q21.31 microdeletion, 6q terminal deletion, 15q inv dup syndrome, 2q24.4 deletion, Xp11.22-11.23 duplication, 15q13.3 microdeletion, 1p36 terminal deletion, 5q14.3 microdeletion, and Xq28 duplication. The papers reviewed did not identify any specific interictal electroencephalographic patterns that were unique and significant biomarkers for a given chromosomal microrearrangement. The types of seizures described varied, with both generalized and focal seizures of various morphologies being reported. Patients with chromosomal anomalies may also meet the criteria for specific epileptic syndromes such as Infantile Epilepsy Spasms Syndrome (IESS, West syndrome): 16p13.11, 15q13.3 and 17q21.31 microdeletions, 5q inv dup. syndrome; Dravet syndrome (2q24.4 deletion), Lennox-Gastaut syndrome (15q11 duplication. 1q13.3, 5q inv dup.); or Self-Limited Epilepsy with Autonomic Features (SeLEAS, Panayiotopoulos syndrome: terminal deletion of 6q.n), Self-Limited Epilepsy with Centrotemporal Spikes (SeLECT): fragile X syndrome. It is essential to better characterize groups of patients to more accurately define patterns of epilepsy and EEG abnormalities. This could lead to new treatment strategies. Future research is required to better understand epileptic syndromes and chromosomal rearrangements. PLAIN LANGUAGE SUMMARY: This paper presents EEG recording abnormalities in patients with various gene abnormalities that can cause epilepsy. The authors summarize these EEG variations based on a literature review to see if they occur frequently enough in other chromosomal abnormalities (in addition to those already known) to be a clue for further diagnosis.