Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review.

Background: TRAF7-related cardiac, facial, and digital anomalies with developmental delay (CAFDADD), a multisystemic neurodevelopmental disorder caused by germline missense variants in the TRAF7 gene, exhibits heterogeneous clinical presentations.

Methods: We present a detailed description of 11 new TRAF7-related CAFDADD cases, featuring eight distinct variants, including a novel one.

Results: Phenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac defects.

Clinical and Genetic Analysis of Patients With TK2 Deficiency.

Objectives: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive disorder that stems from a perturbation of the mitochondrial DNA maintenance. Nucleoside treatment has recently shown promise as a disease-modifying therapy. TK2d was initially associated with rapidly progressive fatal myopathy in children featuring mitochondrial DNA depletion.

Two siblings with uncombable hair syndrome: A new pathogenic variant.

Two siblings presented with straw-colored, frizzy, and wiry hair. They had no associated abnormalities and no family history of abnormal hair. Trichoscopy showed the longitudinal groove in the hair shafts, characteristic of uncombable hair syndrome.

Enrichment of Immune Dysregulation Disorders in Adult Patients with Human Inborn Errors of Immunity.

Human inborn errors of immunity (IEI) comprise a group of diseases resulting from molecular variants that compromise innate and adaptive immunity. Clinical features of IEI patients are dominated by susceptibility to a spectrum of infectious diseases, as well as autoimmune, autoinflammatory, allergic, and malignant phenotypes that usually appear in childhood, which is when the diagnosis is typically made. However, some IEI patients are identified in adulthood due to symptomatic delay of the disease or other reasons that prevent the request for a molecular study.

Diagnostic yield of genetic testing in adults with sensorineural hearing loss.

Introduction: The contribution of genetic causes to sensorineural hearing loss (SNHL) in adults is less clear than in children, and genetic diagnosis is still not standardized in adults. In this study we present the genetic results obtained in a cohort of adult patients with SNHL.

Materials And Methods: We included 63 adults with SNHL that received genetic testing between 2019 and 2022.

Genetic diagnosis of childhood sensorineural hearing loss.

Introduction: Congenital/early-onset sensorineural hearing loss (SNHL) is one of the most common hereditary disorders in our environment. There is increasing awareness of the importance of an etiologic diagnosis, and genetic testing with next-generation sequencing (NGS) has the highest diagnostic yield. Our study shows the genetic results obtained in a cohort of patients with bilateral congenital/early-onset SNHL.

Cystic phenotype and chronic kidney disease in autosomal dominant Alport syndrome.

Background: Autosomal dominant Alport Syndrome (ADAS), also known as thin basement membrane disease (TBMD), is caused by pathogenic variants in the COL4A3 and COL4A4 genes. A cystic phenotype has been described in some patients with TBMD, but no genetic studies have been performed. We conducted a genetic and radiologic investigation in a cohort of ADAS patients to analyze the prevalence of multicystic kidney disease (MKD) and its association with chronic kidney disease (CKD).

Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the Gene Associated with Autosomal Recessive Erythrokeratoderma.

Hereditary palmoplantar keratodermas (PPKs) are a clinically and genetically heterogeneous group of disorders characterized by excessive epidermal thickening of palms and soles. Several genes have been associated with PPK including , a gene encoding a crucial component of desmosomes that has been associated with dominant and recessive keratoderma. We report a patient with recessive erythrokeratoderma (EK) in which whole exome sequencing (WES) prioritized by human phenotype ontology (HPO) terms revealed the presence of the novel variant c.

TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.

Background: TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance.

Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

Background: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving cause KBG syndrome, but no genotype-phenotype correlation has been reported.

Methods: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire.

New Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome cases are caused by the presence of a nonsense variant in compound heterozygosity with the pathogenic repeat expansion in the RFC1 gene.

The biallelic pathogenic repeat (AAGGG) intronic expansion in the RFC1 gene has been recently described as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and as a major cause of late-onset ataxia. Since then, many heterozygous carriers have been identified, with an estimated allele frequency of 0.7% to 4% in the healthy population.

Expanding the Phenotypic Spectrum of Alazami Syndrome: Two Unrelated Spanish Families.

Alazami syndrome is a rare disorder with an autosomal recessive inheritance caused by pathogenic biallelic variants in the gene. Clinically, it is mainly characterized by short stature, intellectual disability, and dysmorphic facial features. However, the phenotype is not yet well-defined because less than 50 cases have been described to date.

Alström syndrome: Two clinical cases with two novel pathogenic variants.

Purpose: To report two clinical cases of Alström syndrome (AS) with novel pathogenic variant of the ALMS1 gene not previously reported.

Case Description: Patient 1 was a 6-year-old female presenting with poor vision. Ophthalmic examination only showed a visual field (VF) with diffusely decreased sensitivity in both eyes.

Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy.

Somatic mutations in the ten-eleven translocation methylcytosine dioxygenase 2 gene (TET2) have been associated to hematologic malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene.

Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.

Lethal congenital contracture syndrome 11 (LCCS11) is caused by homozygous or compound heterozygous variants in the gene on chromosome 15q21. encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report a fetus with ultrasound alterations detected at 28 weeks of gestation.

Hereditary cerebral small vessel disease: Assessment of a HTRA1 variant using protein stability predictors and 3D modelling.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an autosomal recessive vascular disorder caused by biallellic variants in HTRA1. Recently, it has been reported that several heterozygous mutations in HTRA1 are responsible for a milder late-onset cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. The majority of them are missense that affects the Htr1A protease activity due to a dominant-negative effect caused by defective trimerization or monomer activation.

Heterozygous and Homozygous Variants in Gene in Alzheimer's Disease Patients: Clinical, Neuroimaging and Neuropathological Findings.

In the last few years, the SORL1 gene has been strongly implicated in the development of Alzheimer’s disease (AD). We performed whole-exome sequencing on 37 patients with early-onset dementia or family history suggestive of autosomal dominant dementia. Data analysis was based on a custom panel that included 46 genes related to AD and dementia.

Early-Onset Dementia Associated with a Heterozygous, Nonsense, and de novo Variant in the MBD5 Gene.

The haploinsufficiency of the methyl-binding domain protein 5 (MBD5) gene has been identified as the determinant cause of the neuropsychiatric disorders grouped under the name MBD5-neurodevelopment disorders (MAND). MAND includes patients with intellectual disability, behavioral problems, and seizures with a static clinical course. However, a few reports have suggested regression.

First female with Allan-Herndon-Dudley syndrome and partial deletion of X-inactivation center.

Allan-Herndon-Dudley is an X-linked recessive syndrome caused by pathogenic variants in the SLC16A2 gene. Clinical manifestations are a consequence of impaired thyroid metabolism and aberrant transport of thyroid hormones to the brain. Carrier females are generally asymptomatic and may show subtle symptoms of the disease.

Expanding the clinical and genetic spectrum of -related disorders in family with personality disorder and frontotemporal dementia.

-variants associated with frontotemporal lobar degeneration have been described recently. In this study, we investigated a heterozygous in-frame duplication c.436_462dup p.

Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test.

Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs.

First patient with mosaic NOTCH3 gene pathogenic variant. Unrevealed mosaicisms and importance of their detection.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused predominantly by pathogenic variants in NOTCH3 gene. Neither germline nor somatic mosaicism has been previously published in NOTCH3 gene. CADASIL is inherited in an autosomal dominant manner; only rare cases have been associated with de novo pathogenic variants.