American Journal of Medical Genetics Part A最新文献

Non-mosaic trisomy 9 (NMTS9) is a rarely described chromosomal abnormality because most affected pregnancies result in first trimester spontaneous abortions, although survival to delivery is possible. In contrast, the phenotypic features of mosaic trisomy 9 have been well described in the literature as these individuals can survive to birth and beyond. Therefore, a better understanding of the phenotypic spectrum of NMTS9 is needed to provide appropriate perinatal counseling. The phenotype from three fetal and one neonatal case of NMTS9, as defined by chromosome analysis in multiple tissues, is consistent with the existing literature and includes narrow forehead, midface hypoplasia, microphthalmia, clouded corneas, blepharophimosis, rounded nasal tip, broad/prominent nasal bridge, low-set ears with and without malformations, short and broad neck, cerebellar abnormalities, a wide range of cardiac anomalies including ventricular and atrial septal defects as well as valve dysplasia, congenital diaphragmatic hernia, hydronephrosis, and hypoplastic genitalia, multiple contractures, multiple dislocations, and talipes equinovarus. We also report an expansion of the cardiac, genitourinary, and renal phenotypes. This combined phenotype based on prenatal imaging and fetal/postnatal autopsy further delineates the clinical phenotype of NMTS9.

Patients with 22q11.2 deletion syndrome (22q11DS) are predisposed to obstructive sleep apnea (OSA) due to an abnormal craniofacial anatomy with pharyngeal hypotonia, retrognathia, micrognathia, and glossoptosis. The aim of the study was to describe the prevalence and management of OSA in a cohort of children with 22q11DS. All patients with 22q11DS seen at the national reference center of craniofacial anomalies at Necker-Enfants malades hospital (Paris, France) between April 2014 and April 2024 had a systematic respiratory polygraphy (PG) in room air. Clinical data, PGs, and subsequent OSA management were retrospectively analyzed. The data of 52 patients were analyzed. Associated disorders were common, with 79% of the patients having an upper airway anomaly, 58% a cardiopathy, and 30% a pulmonary disease. Mean age at baseline PG was 6.6 ± 4.6 (0.1-18) years. Twelve (23%) patients had an adenoidectomy and/or tonsillectomy, and 10 (19%) patients a posterior flap pharyngoplasty prior to baseline PG. Four patients were treated with continuous positive airway pressure (CPAP) and 2 patients with a cardiopathy were treated with long-term oxygen therapy prior to baseline PG. Mean AHI was 4.0 ± 9.1 (0-43) events/h, with 24 (46%) patients having OSA, with 15 (29%) having mild OSA, 5 (9%) moderate OSA, and 4 (8%) severe OSA. A young age (p = 0.003), an immune deficiency (p = 0.018) and a pulmonary disease (p = 0.028) were more common in patients with OSA as compared to those without OSA. On follow-up, OSA improved after upper airway surgery in 4 patients or spontaneously, with only 2 patients requiring CPAP for persistent moderate OSA. In conclusion, the prevalence of OSA in children with 22q11DS is high. OSA severity is mainly mild except in infants aged < 1 year with an immune deficiency and a pulmonary disease being more common in patients with OSA as compared to those without OSA.

48,XXYY syndrome is a rare sex chromosome aneuploidy (SCA) condition affecting 1 in 18,000-40,000 male births. Clinical features include tall stature, hypergonadotropic hypogonadism (testosterone deficiency), infertility, developmental delays, learning disabilities, and intellectual impairment. Co-occurring behavior and mental health challenges are common in this population, with high rates of attention-deficit hyperactivity disorder (ADHD), anxiety, depression, sleep disorders, irritability, and aggressive behaviors. We evaluated psychotropic medication use by parent report and retrospective chart review. Treatment success was defined as a positive response per parent report, positive clinician rating, or a treatment duration of at least 6 months. Nearly three-quarters of participants (71/101) with a median age of 15.9 (range 4.5-38 years) had received psychotropic medications. The most common medication classes used were stimulant ADHD medications (78.9% of those with medication use), with a median age of first use of 9 years ([IQR] 7, 11 years), followed by anti-anxiety/antidepressant medications (60.6%), with a median age of first use of 10 years ([IQR] 8, 14 years). Treatment success rates ranged from 43.9% to 84.2% for individual medication trials. Subsequent trials of medications within the same class improved success rates per person in all medication classes except for sleep and mood stabilizer medications. Treatment failure due to side effects was greatest among neuroleptics/atypical antipsychotics, whereas treatment failure due to inefficacy was greatest among anti-anxiety/antidepressants and mood stabilizers. The findings of this study suggest that psychotropic medications targeting behavior and mental health are common and overall helpful for individuals with 48,XXYY.

The cohesin complex plays crucial roles in DNA repair, chromatid separation, and gene transcription regulation. Pathogenic variants in cohesins or dysfunctional transcriptional regulators lead to cohesinopathies, a broader group of disorders including Cornelia de Lange Spectrum (CdLSp), for which the prevalence of cancer cases remains unclear. Here, we aimed to assess the prevalence of oncological events in CdLSp and elucidate the role of cohesin variants in cancer predisposition. We developed a custom next-generation sequencing (NGS) panel targeting predisposition and pathogenic genes, which we applied on N = 120 samples of pediatric patients with acute lymphoblastic leukemia (ALL), identifying 11 out of 229 total-10 germline and 1 somatic-variants in cohesin genes. Data of N = 205 brain tumors were extracted by bioinformatic analysis of data from open-source databases carrying 19 somatic variants. In a cohort of 54 CdLSp patients, the largest cohort from a single center, with a median age of 13 years, the hypothesis of an increased prevalence of cancer in CdLSp was not confirmed. Our findings highlight a significant involvement of germline NIPBL variants in CdLSp, whereas RAD21 and STAG1/2 are predominantly found as somatic variants in neoplasms. However, a distinct genetic or molecular pattern distinguishing variants leading to CdLSp from tumors was not identified. Hence, we advocate for further investigation into the relationship between cohesin variants and cancer predisposition in a larger cohort of patients, with a longer observation time and including different types of malignancies, with more focus on epigenetic approaches.

Beckwith-Wiedemann spectrum (BWSp) is an overgrowth disorder caused by (epi)genetic alterations in chromosome 11p15. This study aimed to develop BWSp-specific growth charts and explore genotype/phenotype correlations with respect to growth. Heights, weights, and head circumferences were retrospectively collected from 581 individuals with BWSp from the Netherlands, Italy, and the United States. The Generalized Additive Models for Location, Scale, and Shape (GAMLSS) method was employed to develop the following charts: height-for-age, weight-for-age, BMI-for-age, and head circumference-for-age for males and females. Mean height, weight, and head circumference were compared with those of the growth charts generated by the World Health Organization (WHO). Individuals with BWSp show enhanced growth rate during puberty and adolescence, and all growth parameters were increased compared to WHO charts. Mean modeled height at 18 years of age was 180.6 cm for males and 166.3 cm for females (+0.6 SDS and +0.5 SDS, respectively, compared to WHO charts). In conclusion, these growth charts offer valuable insights into the growth patterns in BWSp individuals and provide a key tool for personalized medical care for individuals with BWSp.

Difficulties with feeding and digestion are common in individuals with CHARGE syndrome. Animal models with CHD7 gene variants demonstrate abnormal gut innovation and dysmotility. Our pilot study evaluated whether individuals with CHARGE syndrome have differences in their gut microbiome compared to unaffected siblings. Participants between the ages of 2-18 were recruited from Atlantic Canada with a confirmed genetic diagnosis of CHARGE syndrome. Gut Microbiome DNA analysis was performed on stool samples using 16S ribosomal RNA (rRNA) gene sequences. The PASSFP and PEDSQL served as GI symptom questionnaires. Eleven participants completed this study with one twin pair (CHARGE syndrome = 7, sibling controls = 4). The mean percent abundance for the four most common phyla in individuals with CHARGE versus Controls showed a trend towards increased Bacteroidetes, Proteobacteria, and a decrease in Firmicutes and Actinobacteria but was not significant. Microbiome comparisons based on abnormal (< 77) and normal ( $\ge$  77) GI scores, found significantly elevated Bacteroidetes (p = 0.042, 59.5% ± 15.1% vs. 33.1% ± 14.6%) and decreased Firmicutes (p = 0.042, 37.5% ± 15.9% vs. 62.4% ± 14.0%) with abnormal scores. Alpha diversity did not differ with either disease or GI symptom scores. Our data showed that, although there was a trend in changes in the gut microbiome in individuals with CHARGE compared to unaffected siblings, this change appears to be related to the severity of GI symptoms and not necessarily CHARGE itself, as differences were more pronounced in individuals with more difficulties with feeding and GI symptoms.

We report a female patient with a de novo deep intronic variant in NSD1 detected by whole genome sequencing (WGS). RNA-seq revealed the creation of a novel exon (exonization), and methylation analysis showed an episignature pattern overlapping with Sotos syndrome patients with well-established pathogenic NSD1 variants, confirming the diagnosis of Sotos syndrome. This patient reinforces the importance of WGS in cases with clear clinical phenotypes and the emerging role of methylation profiling as a diagnostic tool in individuals where conventional approaches failed.

Arthrogryposis multiplex congenita (AMC) represents a large, rare group of congenital conditions. This study addressed major challenges in AMC research posed by the lack of systematic frameworks for data collection and the use of inconsistent terminologies and text descriptions. We aimed to systematically review the Human Phenotype Ontology (HPO) terms, encode AMC phenotypic traits as HPO terms, and pilot test the encoding process in a cohort of children with AMC. An international consensus-based dataset for AMC was used to extract phenotypic traits from the fetal period to adulthood. The encoding process was developed by an international expert panel to expand and revise HPO ontology for joint contractures, as the main characterizing traits in AMC. Using a pre-tested mapping algorithm, the HPO mapping process resulted in a 62% complete match, a 12% incomplete match, and a 26% no match. The encoding process included 37 new terms and annotations and 13 re-structures across 10 different joints. The implemented annotations significantly increased the number of available HPO terms for joint contractures in a cohort of children with AMC (p-value = 0.04). Our encoding and annotation approach may be used as a blueprint for systematic HPO (re)annotations for musculoskeletal and non-musculoskeletal phenotypic traits of AMC.