1p36 Deletion Research Articles

Polyarticular juvenile idiopathic arthritis with Madelung deformity and arthritis mutilans in 18p deletion syndrome.

Polyarticular juvenile idiopathic arthritis with Madelung deformity and arthritis mutilans in 18p deletion syndrome.

Diagnostic Accuracy Performance of Fluorescence In Situ Hybridization (FISH) for Biliary Strictures: A Systematic Review and Meta-Analysis.

Background and Aims: This systematic review and meta-analysis aims to compare the performance of UroVysion® FISH based on the different definitions of a positive result used in published literature with the goal of determining the optimal FISH definition for detecting pancreaticobiliary malignancy. Methods: A systematic literature search identified studies from database inception to Sept 2024 that evaluated the diagnostic performance of FISH in determining malignancy among patients with biliary strictures. All thresholds for positive FISH, as defined by the individual study, were included in this review. Subgroup analysis was performed based on the definitions of positive FISH as follows: (1) polysomy only; (2) polysomy, tetrasomy, or trisomy; and (3) polysomy or 9p deletion. Results: Eighteen studies comprising 2516 FISH specimens were analyzed, including 1133 (45.0%) with malignancy. Using a threshold for positivity as defined in individual studies, the overall sensitivity of FISH was 57.6% (95% confidence interval [CI], 49.4-65.4%), and the overall specificity was 87.8% (95% CI, 79.2-93.2%). Subgroup analysis showed that polysomy as the threshold for positive FISH yielded a sensitivity of 49.4% (95% CI, 43.2-55.5%), with an increased specificity of 96.2% (95% CI, 92.7-98.1%), while polysomy + tetrasomy/trisomy as positive FISH resulted in an increased sensitivity of 64.3% (95% CI 55.4-72.2%) but a decreased specificity of 78.9% (95% CI 64.4-88.5%). The addition of 9p deletion to polysomy as the criteria for a positive test resulted in a non-significant increase in sensitivity (54.7% (95% CI 42.4-66.5%) while maintaining specificity (95.1% (95% CI 84.0-98.6%). Conclusions: Based on these findings, polysomy only or polysomy/9p deletion should be considered as the criterion for defining a positive FISH test to improve diagnostic sensitivity while maintaining high specificity.

DNA methylation dysregulation patterns in the 1p36 region instability.

In the monosomy 1p36 deletion syndrome, the role of DNA methylation in the genomic stability of the 1p36 region remains elusive. We hypothesize that changes in the methylation pattern at the 1p36 breakpoint hotspot region influenced the chromosomal breakage leading to terminal deletions. From the monosomy 1p36 material collection, four cases with 4.0 to 5.5Mb terminal deletions and their parents were investigated. DNA samples were assessed by targeted bisulfite sequencing (NimbleGen SeqCap Epi) to examine DNA methylation status in the 1p36 hotspot region at single-base resolution as compared to the chromosomal hotspot regions, 9p22, 18q21.1, and 22q11.2. Additionally, in in silico assessment, the mean GC content of various classes of repeats in the genome and especially in the breakpoint regions was evaluated. A complex landscape of DNA methylation in the 1p36 breakpoint hotspot region was found. Changes in DNA methylation level in the vicinity of the breakpoint in the child's DNA when compared to parents' and control DNA were observed, with a shift from 15.1 to 70.8% spanning the breakpoint region. In the main classes of evaluated repeats, higher mean GC contents in the 1p36 breakpoint region (47.06%), 22q11.2 (48.47%), and 18q21.1 (44.21%) were found, compared to the rest of the genome (40.78%). The 9p22 region showed a lower GC content (39.42%) compared to the rest of the genome. Both dysregulation of DNA methylation and high GC content were found to be specific for the 1p36 breakpoint hotspot region suggesting that methylation abnormalities could contribute to aberrations at 1p36.

Prenatal diagnosis and genetic analysis of two fetuses with Wolf-Hirschhorn syndrome

To explore the prenatal ultrasound phenotype and genetic basis of two fetuses with Wolf-Hirschhorn syndrome (WHS). A retrospective analysis was conducted on the ultrasound imaging data of two fetuses suspected for WHS at the Prenatal Diagnostic Center of Qingyuan People's Hospital in July 2017 and August 2019, respectively. Amniotic fluid samples of the two fetuses were subjected to chromosomal karyotyping and chromosomal microarray analysis (CMA). This study was approved by the Qingyuan People's Hospital (Ethics No. IRB-2022-064). Prenatal ultrasound examination of the two fetuses had consistently revealed WHS-associated traits including intrauterine growth restriction (IUGR), craniofacial abnormalities and cardiovascular anomalies. Karyotyping analysis suggested that both fetuses had harbored cryptic chromosomal translocations involving partial deletion of 4p. And parental verification revealed that it was de novo for fetus 1 and paternal for fetus 2. CMA has confirmed that fetus 1 had an approximately 8.7 Mb deletion at 4p16.3p16.1 and a 6.8 Mb duplication at 8p23.1p23.1, whilst fetus 2 had a 20.05 Mb deletion at 4p16.3p15.31 and a 7.66 Mb duplication at 9p24.3p24.1. The karyotype of fetus 1 was determined as 46,XN,der(4)t(4;8)(p16.1;p23.1)dn.arr[hg19]4p16.3p16.1(68345_8721580)×1, 8p23.3p23.1(158048_6933745)×3, and that of fetus 2 was determined as 46,XN,der(4)t(4;9)(p15.3;p24)pat.arr[hg19]4p16.3p15.31(68345_20116061)×1, 9p24.3p24.1(208454_7868292)×3. The 4p deletion is probably the main cause for the WHS phenotype in both fetuses. WHS should be suspected when IUGR, renal anomalies, craniofacial and cardiovascular abnormalities are detected upon prenatal ultrasound screening.

Monozygotic triplets with juvenile-onset autoimmunity and 18p microdeletion involving PTPRM.

Abnormal gene dosage from copy number variants has been associated with susceptibility to autoimmune disease. This includes 18p deletion syndrome, a chromosomal disorder with an estimated prevalence of 1 in 50,000 characterized by intellectual disability, facial dysmorphology, and brain abnormalities. The underlying causes for autoimmune manifestations associated with 18p deletions, however, remain unknown. Our objective was to investigate a distinctive case involving monozygotic triplets concordant for developmental delay, white matter abnormalities, and autoimmunity, specifically juvenile-onset Graves' thyroiditis. By chromosomal microarray analysis and whole genome sequencing, we found the triplets to carry a de novo interstitial 5.9Mb deletion of chromosome 18p11.31p11.21 spanning 19 protein-coding genes. We conducted a literature review to pinpoint genes affected by the deletion that could be associated with immune dysregulation and identified PTPRM as a potential candidate. Through dephosphorylation, PTPRM serves as a negative regulator of STAT3, a key factor in the generation of Th17 cells and the onset of specific autoimmune manifestations. We hypothesized that PTPRM hemizygosity results in increased STAT3 activation. We therefore performed assays investigating PTPRM expression, STAT3 phosphorylation, Th1/Th2/Th17 cell fractions, Treg cells, and overall immunophenotype, and in support of the hypothesis, our investigations showed an increase in cells with phosphorylated STAT3 and higher levels of Th17 cells in the triplets. We propose that PTPRM hemizygosity can serve as a contributing factor to autoimmune susceptibility in 18p deletion syndrome. If confirmed in unrelated 18p/PTPRM deletion patients, this susceptibility could potentially be treated by targeted inhibition of IL-17.

A Unique Derivative Chromosome 4 with a Predominant 4p16.3 Microduplication Phenotype and a Literature Review

Introduction: Constitutional structural abnormalities affecting chromosome 4 result in variable distinct phenotypic traits including duplication 4p syndrome, deletion 4p or Wolf-Hirschhorn syndrome (WHS), deletion 4q and duplication 4q syndromes. Complex rearrangements involving both chromosome 4 arms are very rarely reported with different break points occurring within regions of 4p13-p16 and 4q32-35. They most commonly occur in familial cases due to parental pericentric inversion resulting in a recombinant chromosome 4 “rec(4).” The clinical picture is dependent on the size and type of copy number imbalance and the genes involved. Methods: We report on a female patient with delayed developmental milestones and lower limb anomalies, who carried a de novo unique type of complex rearrangement affecting both chromosome 4 arms, diagnosed by karyotype and fluorescence in situ hybridization analysis and chromosomal microarray (CMA). Results: The chromosome 4 rearrangement involved three copy number alterations, consisting of a terminal 1.17 Mb 4p16.3 deletion with a contiguous proximal 1.8 Mb 4p16.3 duplication, including the Wolf-Hirschhorn critical (WHSC) region, and an inverted 27 Mb terminal 4q32-35.2 duplication attached to terminal 4p. The patient’s predominant phenotype was consistent with 4p16.3 microduplication syndrome. The rearrangement occurred as a de novo abnormality, and thus it was designated as a derivative chromosome 4. To the best of our knowledge, this complex type of chromosome 4 rearrangement has not been reported so far. Conclusion: The present report adds to the scarce 4p16.3 microduplication syndrome reports and emphasizes the role of WHSC region in the syndromic phenotype. It also reveals the importance of CMA in detecting subtle copy number variations (CNVs) that could be dominantly reflected on the phenotype, which is very important in patients’ management and family counselling.

A Child Carrying a Large Deletion in the 10p.15.3-p12.31 Region

Partial deletion of 10p is a rare disorder. Common features of this disorder include intellectual disability, developmental delay, dysmorphic features, hypoparathyroidism, deafness, and renal anomalies, but the phenotypes can vary between patients. We report an infant girl presented with global developmental delay, distinctive facial features with cleft lip, congenital exotropia, laryngomalacia, atrial septal defect, and sensorineural hearing loss. 46, XX, del (10p→ter) was observed on the G-banded analysis. A chromosomal microarray was performed to obtain more detail on the deletion size and gene involvement that might be related to the clinical phenotypes, medical problems, and management. The deletion involved the region of 10p15.3–p12.31, with an approximate size of 19.528739 Mb. The size of deletion could determine the variability in phenotypes, and microarray is necessary to comprehend the deletion size and gene involvement better.

Estimating prevalence of rare genetic disease diagnoses using electronic health records in a children’s hospital

Rare genetic diseases (RGDs) affect a significant number of individuals, particularly in pediatric populations. This study investigates the efficacy of identifying RGD diagnoses through electronic health records (EHRs) and natural language processing (NLP) tools, and analyzes the prevalence of identified RGDs for potential underdiagnosis at Cincinnati Children's Hospital Medical Center (CCHMC). EHR data from 659,139 pediatric patients at CCHMC were utilized. Diagnoses corresponding to RGDs in Orphanet were identified using rule-based and machine learning-based NLP methods. Manual evaluation assessed the precision of the NLP strategies, with 100 diagnosis descriptions reviewed for each method. The rule-based method achieved a precision of 97.5% (95% CI: 91.5%, 99.4%), while the machine-learning-based method had a precision of 73.5% (95% CI: 63.6%, 81.6%). A manual chart review of 70 randomly selected patients with RGD diagnoses confirmed the diagnoses in 90.3% (95% CI: 82.0%, 95.2%) of cases. A total of 37,326 pediatric patients were identified with 977 RGD diagnoses based on the rule-based method, resulting in a prevalence of 5.66% in this population. While a majority of the disorders showed a higher prevalence at CCHMC compared with Orphanet, some diseases, such as 1p36 deletion syndrome, indicated potential underdiagnosis. Analyses further uncovered disparities in RGD prevalence and age of diagnosis across gender and racial groups. This study demonstrates the utility of employing EHR data with NLP tools to systematically investigate RGD diagnoses in large cohorts. The identified disparities underscore the need for enhanced approaches to guarantee timely and accurate diagnosis and management of pediatric RGDs.

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

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. 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. 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. 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.

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.

ПАРАНЕОПЛАСТИЧЕСКИЙ НЕВРОЛОГИЧЕСКИЙ СИНДРОМ У РЕБЕНКА С НЕЙРОБЛАСТОМОЙ: КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

Paraneoplastic syndromes are of particular difficulties in establishing a timely diagnosis of a malignant tumor esp. in cases when the decease development is occurred chronologically much earlier than the appearance of its specific symptoms and the neoplasm growth’s first signs. And the clinical manifestation can be represented solely by an isolated clinic of paraneoplastic syndrome, which in its turn is much alike the symptoms of the paraneoplastic neurological syndrome (PNS). Authors represent a clinical case of a severe PNS coupled with the central nervous system (CNS) lesion, mainly the cerebellum, which was manifested clinically by ataxia, tremor, myoclonus, dysartria, cognitive and mental impairment and psychotic disorders, which in its turn had delayed the timely diagnosis of neuroblastoma (left-sided intermixed adrenal ganglioneuroblastoma with metastatic tumors in ipsilateral lymph nodes and paranephric fat, deletion 1q, deletion 1p36 and MYCN amplification - all negative and INSS stage 2B) in a 5 y/o male patient. No ‘classical’ opsoclonus-myoclonus was a matter of diagnosis due to the opsoclonus absence during the whole disease course. This clinical case observation publication is having a practical purpose of pinning attention to paraneoplastic syndromes among practitioners of wide spectrum: neurologists, infectionists and pediatricians.

The relationship between vocabulary and grammar in two children with 5p deletion syndrome

ABSTRACT 5p deletion syndrome is a rare genetic condition associated with severe speech and language problems. In general, research on speech and language skills is scarce, but there is more knowledge on phonetic and phonological skills than on lexical and grammatical skills. And till now no studies have addressed the relationship between grammar and vocabulary. Therefore, in this study, we address aspects of this relation based on longitudinal parent-reported data (MacArthur-Bates Communicative Development Inventories) from two children with this syndrome aged 2;0–7;3, and 1;11–7;1, respectively. We examine the development of the vocabulary size in each child, seen in relation to the development of grammar (inflections, combinations of words, complexity, and productivity), and see to what extent they can be compared to typically developing children. Results show that they follow a similar pattern to typically developing children but are delayed and have slightly different individual profiles.

Tremulous Dystonia Due to GNAL Haploinsufficiency Caused by 18p Deletion Syndrome.

Tremulous Dystonia Due to GNAL Haploinsufficiency Caused by 18p Deletion Syndrome.

Prenatal diagnosis of a fetus with 1p36 deletion syndrome and 3p26.3p25.2 duplication

To explore the characteristics of a fetus with chromosome 1p36 deletion syndrome and 3p26.3p25.2 duplication. A pregnant woman who had attended the Genetic Counseling Clinic of Linyi People's Hospital on February 22, 2022 and her fetus were selected as the study subjects. Clinical data were collected. Chromosomal karyotyping, fluorescence in situ hybridization (FISH) and chromosomal microarray analysis (CMA) were carried out for the prenatal diagnosis. Ultrasonography at 24th gestational week revealed that the fetus had ventricular septal defect, single umbilical artery, and slight widening of left lateral ventricle (12 mm). The woman was found to have a karyotype of 46,XX,t(1;3)(p36.22;p25.2), and the result of FISH was t(1;3)(3pter+,1qter+;1pter+,3qter+). The fetus was found to have a karyotype of 46,X?,add(1)(p36), and CMA confirmed that it has a 9.0 Mb deletion at 1p36.33p36.22 and a 12.6 Mb duplication at 3p26.3p25.2. Combining the maternal karyotype, the molecular karyotype of the fetus was determined as 46,X?,der(1)t(1;3)(p36.22;p25.2)mat.arr[hg19]1p36.33p36.22(849467_9882666)×1, 3p26.3p25.2(61892_12699607)×3, with the former known to be associated with 1p36 deletion syndrome. The fetus was diagnosed with 1p36 deletion syndrome, and its 1p36.33p36.22 deletion and 3p26.3p25.2 duplication had both derived from the balanced translocation carried by its mother.

Prenatal diagnosis of 18p deletion and 8p trisomy syndrome: literature review and report of a novel case

18p deletion syndrome constitutes one of the most frequent autosomal terminal deletion syndromes, affecting one in 50,000 live births. The syndrome has un-specific clinical features which vary significantly between patients and may overlap with other genetic conditions. Its prenatal description is extremely rare as the fetal phenotype is often not present during pregnancy. Trisomy 8p Syndrome is characterized by heterogenous phenotype, with the most frequent components to be cardiac malformation, developmental and intellectual delay. Its prenatal diagnosis is very rare due to the unspecific sonographic features of the affected fetuses. We present a very rare case of a fetus with multiple anomalies diagnosed during the second trimester whose genomic analysis revealed a 18p Deletion and 8p trisomy Syndrome. This is the first case where this combination of DNA mutations has been described prenatally and the second case in general. The presentation of this case, as well as the detailed review of all described cases, aim to expand the existing knowledge regarding this rare condition facilitating its diagnosis in the future.

Novel copy number variations and phenotypes of infantile epileptic spasms syndrome.

We summarize the copy number variations (CNVs) and phenotype spectrum of infantile epileptic spasms syndrome (IESS) in a Chinese cohort. The CNVs were identified by genomic copy number variation sequencing. The CNVs and clinical data were analyzed. 74 IESS children with CNVs were enrolled. 35 kinds of CNVs were identified. There were 11 deletions and 5 duplications not reported previously in IESS, including 2 CNVs not reported in epilepsy. 87.8% were de novo, 9.5% were inherited from mother and 2.7% from father. Mosaicism occurred in one patient with Xq21.31q25 duplication. 16.2% (12/74) were 1p36 deletion, and 20.3% (15/74) were 15q11-q13 duplication. The age of seizure onset ranged from 17 days to 24 months. Seizure types included epileptic spasms, focal seizures, tonic seizures, and myoclonic seizures. All patients displayed developmental delay. Additional features included craniofacial anomaly, microcephaly, congenital heart defects, and hemangioma. 29.7% of patients were seizure-free for more than 12 months, and 70.3% still had seizures after trying 2 or more anti-seizure medications. In conclusion, CNVs is a prominent etiology of IESS. 1p36 deletion and 15q duplication occurred most frequently. CNV detection should be performed in patients with IESS of unknown causes, especially in children with craniofacial anomalies and microcephaly.

Conventional and molecular cytogenetic characterization of a Moroccan patient with WAGR syndrome

BackgroundWAGR syndrome is a rare genetic disorder characterized by a de novo deletion of 11p13 and is usually clinically associated with Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation (W-A-G-R). Although the genotypic defects in WAGR syndrome have been well established. The congenital aniridia is caused, in nearly 90% of cases by mutations in the gene PAX6. In the face of congenital aniridia, it is imperative to specify whether it falls within the scope of a WAGR syndrome or if it is an isolated congenital aniridia or inherited by performing karyotype, FISH (Fluorescence In Situ Hybridization) or a CGH array for genetic counseling.Case presentationWe report here a case of genetic testing for newborn with aniridia, to detect 11p13 rearrangements, using karyotyping and CGH array to complete picture of the chromosomal deletions and breakpoints in aniridia. Results show either a loss of 3811.196 kb on chromosome 11 delimited by the bands p14.1 and p13 with formula or a loss of a 1867.287 kb on chromosome 18 fragment delimited by q21.33 and q22.1 bands, that has not been detected by karyotype analysis.ConclusionsCytogenetics screening is a good strategy for the genetic diagnosis of aniridia and associated syndromes, allowing for a better identification of breakpoints. Our results underline the clinical importance of performing exhaustive and accurate analysis of chromosomal rearrangements for patients with aniridia, especially newborns to improve survival and quality of life for affected individuals.

Chromosomal mapping of a major genetic locus from Agropyron cristatum chromosome 6P that influences grain number and spikelet number in wheat.

A novel locus on Agropyron cristatum chromosome 6P that increases grain number and spikelet number was identified in wheat-A. cristatum derivatives and across 3 years. Agropyron cristatum (2n = 4x = 28, PPPP), which has the characteristics of high yield with multiple flowers and spikelets, is a promising gene donor for wheat high-yield improvement. Identifying the genetic loci and genes that regulate yield could elucidate the genetic variations in yield-related traits and provide novel gene sources and insights for high-yield wheat breeding. In this study, cytological analysis and molecular marker analysis revealed that del10a and del31a were wheat-A. cristatum chromosome 6P deletion lines. Notably, del10a carried a segment of the full 6PS and 6PL bin (1-13), while del31a carried a segment of the full 6PS and 6PL bin (1-8). The agronomic characterization and genetic population analysis confirmed that the 6PL bin (9-13) brought about an increase in grain number per spike (average increase of 10.43 grains) and spikelet number per spike (average increase of 3.67) over the three growing seasons. Furthermore, through resequencing, a multiple grain number locus was mapped to the physical interval of 593.03-713.89Mb on chromosome 6P of A. cristatum Z559. The RNA-seq analysis revealed the expression of 537 genes in the del10a young spike tissue, with the annotation indicating that 16 of these genes were associated with grain number and spikelet number. Finally, a total of ten A. cristatum-specific molecular markers were developed for this interval. In summary, this study presents novel genetic material that is useful for high-yield wheat breeding initiatives to meet the challenge of global food security through enhanced agricultural production.

Analysis of genetic etiology in a patient with 1p36 deletion syndrome in conjunct with Snijders Blok-Campeau syndrome

To explore the genetic basis for a patient with unexplained developmental delay and special facial features. A male patient admitted to the Maternal and Child Health Care Hospital of Gansu Province on May 27, 2021 due to infertility was selected as the study subject. Clinical data of the patient was collected, and genomic DNA was extracted from peripheral blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing. The patient was found to harbor a 2.54 Mb deletion in 1p36.33p36.32 and a heterozygous c.1123G>C (p.E375Q) variant of the CHD3 gene, neither of which was detected in his parents. The patient was diagnosed with Snijders Blok-Campeau syndrome in conjunct with 1p36 deletion syndrome, which has enabled genetic counseling for his family.

A Comprehensive Review of Syndromic Forms of Obesity: Genetic Etiology, Clinical Features and Molecular Diagnosis.

Syndromic obesity refers to obesity occurring with additional clinical findings, such as intellectual disability/developmental delay, dysmorphic features, and congenital malformations. PURPOSE OF REVIEW: To present a narrative review regarding the genetic etiology, clinical description, and molecular diagnosis of syndromic obesity, which is a rare condition with high phenotypic variability and genetic heterogeneity. The following syndromes are presented in this review: Prader-Willi, Bardet-Biedl, Pseudohypoparathyroidism, Alström, Smith-Magenis, Cohen, Temple, 1p36 deletion, 16p11.2 microdeletion, Kleefstra, SIM1-related, Börjeson-Forssman-Lehmann, WAGRO, Carpenter, MORM, and MYT1L-related syndromes. RECENT FINDINGS: There are three main groups of mechanisms for syndromic obesity: imprinting, transcriptional activity regulation, and cellular cilia function. For molecular diagnostic, methods of genome-wide investigation should be prioritized over sequencing of panels of syndromic obesity genes. In addition, we present novel syndromic conditions that need further delineation, but evidences suggest they have a higher frequency of obesity. The etiology of syndromic obesity tends to be linked to disrupted neurodevelopment (central) and is associated with a diversity of genes and biological pathways. In the genetic investigation of individuals with syndromic obesity, the possibility that the etiology of the syndromic condition is independent of obesity should be considered. The accurate genetic diagnosis impacts medical management, treatment, and prognosis, and allows proper genetic counseling.