A Novel Variant Leading to Lateral Meningocele Syndrome: Prenatal Diagnosis and Possible Expansion of the Phenotype.

Introduction: NOTCH3, one of the four mammalian Notch receptors, acts as a transcriptional activator in a variety of tissues. Variants in lead to distinct phenotypes, depending on variant type and location. Truncating variants in the last exon generate a protein lacking the PEST domain, responsible for degradation, leading to a gain-of-function effect and causing Lateral Meningoceles syndrome (LMS), characterized by dysmorphisms and variable cardiac, skeletal, and connective tissue abnormalities; motor delay may occur, but the cognitive function is usually normal.

Blended Phenotypes in Individuals With Rare Diseases: A Brazilian Case Series.

The growing use of whole exome sequencing and whole genome sequencing in clinical practice has revealed the existence of a group of individuals that do not fit into only one molecular diagnosis. These subjects are those in whom pathogenic or likely pathogenic variants occur in more than one gene, creating "blended phenotypes" There are also genes that warrant reporting, even if they are not associated with the primary phenotype, referred to as 'secondary findings'. In this report, we analyze the prevalence of blended phenotypes in a cohort of 447 individuals who underwent broad genomic sequencing and also present a case series of eight probands who presented multiple diagnoses, generating a mixed phenotype and creating a peculiar clinical situation.

Clinical and Molecular Characterization of Xia-Gibbs Syndrome: Expanding the Phenotypic Spectrum in a Brazilian Cohort.

Xia-Gibbs syndrome (XGS) is a rare intellectual disability (ID) syndrome caused by de novo AHDC1 pathogenic variants. We characterized clinical and molecular features of 16 Brazilian patients with XGS. Patient data were collected through semistructured interviews with family members, reanalysis of previous health and genetic assessments, and clinical reports from physicians.

Plastic Bronchitis in Noonan Syndrome: Further Evidence Suggesting a Higher Risk of Lymphatic Abnormalities in Individuals Harboring Variants in PTPN11 Residue p.Phe285.

Introduction: Noonan syndrome (NS) is a Mendelian phenotype, member of the RASopathies, a group of clinically overlapping multisystem disorders caused by germline variants in the RAS-MAPK signaling pathway genes. Among the clinical findings in NS, lymphatic abnormalities (LAs) are diagnosed in approximately 30%, mostly in individuals harboring variants in and . This genotype-phenotype correlation is not precise, and recent evidence suggests a higher prevalence of LAs in individuals harboring variants on p.

EHMT2 as a Candidate Gene for an Autosomal Recessive Neurodevelopmental Syndrome.

Neurodevelopmental disorders (NDD) comprise clinical conditions with high genetic heterogeneity and a notable enrichment of genes involved in regulating chromatin structure and function. The EHMT1/2 epigenetic complex plays a crucial role in repression of gene transcription in a highly tissue- and temporal-specific manner. Mutations resulting in heterozygous loss-of-function (LoF) of EHMT1 are implicated in Kleefstra syndrome 1 (KS1).

Lifetime Impact Study for Achondroplasia (LISA): Findings from an observational and multinational study focused on health-related quality of life in individuals with achondroplasia in Latin America.

Purpose: The multisystem clinical manifestations and complications of achondroplasia, the most common form of disproportionate short stature, can cause functional impairment and psychosocial burden. The Lifetime Impact Study for Achondroplasia (LISA), aimed to assess health-related quality of life and medical resource utilization among Latin America patients with achondroplasia.

Methods: Data were collected from individuals aged 3 years and above in Argentina, Brazil, and Colombia between 2018 and 2021.

Split Hand-Foot Malformations-Unveiling Unique Molecular Diagnosis From a Brazilian Cohort.

Split hand-foot malformation (SHFM) is a congenital limb malformation affecting primarily the central rays of the hands and/or feet, with variable expressivity, incomplete penetrance and syndromic forms. It is genetically heterogeneous, including point mutations and structural variants in different loci. Five individuals with SHFM were clinically evaluated in a Tertiary Center in Brazil: four of them presented additional, nonskeletal findings, including one individual with split foot, hand syndactyly, and ectodermal findings.

Rare Causes and Differential Diagnosis in Patients With Silver-Russell Syndrome.

Silver-Russell syndrome (SRS) is an imprinting disorder mainly characterized by pre- and postnatal growth restriction. Most SRS cases are due to 11p15.5 loss of methylation (11p15.

Immunocompetent Brain Organoids with Microglia Allow Advanced Aging Research.

Aging is a complex and multifactorial process that significantly affects brain function and health, since it is commonly associated with the emergence of neurodegenerative diseases. Recent advances in stem cell technology have facilitated the development of brain organoids, three-dimensional structures that mimic key aspects of brain architecture and functionality. By incorporating microglia, the resident monocyte-derived immune cells of the central nervous system, immunocompetent brain organoids can provide a more physiologically relevant model for studying brain aging.

The first Brazilian clinical report of Kleefstra syndrome, including semicircular canals agenesis as a possible phenotype expansion.

Objective: to report the first case series of Brazilian children diagnosed with Kleefstra syndrome, present a possible phenotype expansion to the syndrome and to raise physicians' awareness for this rare disease.

Results: seven patients with confirmed KS were evaluated, including 5 males and 2 females. Abnormal prenatal findings were observed in 4 patients.

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.

Novel compound heterozygous ABCA2 variants cause IDPOGSA, a variable phenotypic syndrome with intellectual disability.

The gene for ATP binding cassette subfamily A member 2 (ABCA2) is located at chromosome 9q34.3. Biallelic ABCA2 variants lead to intellectual developmental disorder with poor growth and with or without seizures or ataxia (IDPOGSA).

Clinical Characterization and Underlying Genetic Findings in Brazilian Patients with Syndromic Microcephaly Associated with Neurodevelopmental Disorders.

Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing.

POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies.

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects.

Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants.

Intellectual disability (ID) is an early onset impairment in cognitive functioning and adaptive behavior, affecting approximately 1% of the population worldwide. Extreme skewing of X-chromosome inactivation (XCI) can be associated with ID phenotypes caused by pathogenic variants in the X chromosome. We analyzed the XCI pattern in blood samples of 194 women with idiopathic ID, using the androgen receptor gene (AR) methylation assay.

Nosology of genetic skeletal disorders: 2023 revision.

The "Nosology of genetic skeletal disorders" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms.

Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder.

The SUZ12 gene encodes a subunit of polycomb repressive complex 2 (PRC2) that is essential for development by silencing the expression of multiple genes. Germline heterozygous variants in SUZ12 have been found in Imagawa-Matsumoto syndrome (IMMAS) characterized by overgrowth and multiple dysmorphic features. Similarly, both EZH2 and EED also encode a subunit of PRC2 each and their pathogenic variants cause Weaver syndrome and Cohen-Gibson syndrome, respectively.

Childhood Hypophosphatasia Associated with a Novel Biallelic Variant at the TNSALP Dimer Interface.

The goal of this study was to perform a clinical and molecular investigation in an eight-year-old female child diagnosed with hypophosphatasia (HPP). The proband and her family were evaluated by medical and dental histories, biochemical analyses, radiographic imaging, and genetic analysis of the tissue-nonspecific alkaline phosphatase () gene. A bioinformatic analysis was performed to predict the structural and functional impact of the point mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) molecule and to define their potential contribution to the phenotype.