Autosomal Dominant Intellectual Development Disorder-6 (MRD6) Without Seizures Linked to a De Novo Mutation in the grin2b Gene Revealed by Exome Sequencing: A Case Report of a Moroccan Child.

Autosomal dominant intellectual development disorder-6 (MRD6) arises from a grin2b gene mutation, inducing neurodevelopmental issues. The effects of MRD6 encompass cognitive disabilities, seizures, muscle tone decline, and autism-like traits. Its severity ranges from mild impairment to severe epilepsy. The disorder's rarity is emphasized by roughly 100 reported GRIN2B-related cases, spotlighting the gene's significance in brain development. We present the case of a three-year-old Moroccan boy who was referred to a neuropediatric department for a molecular diagnosis. Initial genetic testing yielded inconclusive results, and subsequent tests for Angelman syndrome and metabolic diseases showed no abnormalities. Given the complexity of the disorder, exome sequencing was employed to identify the underlying genetic cause. Exome sequencing identified a nonsense (STOP) mutation c.3912C>G (p.Tyr1304Ter) in the grin2b gene in the heterozygous state known to be present in MRD6 (Online Mendelian Inheritance in Man (OMIM) 613970). The family segregation study shows that this is a de novo variant, which is confirmed by Sanger sequencing. This variant has not been previously reported in the GnomAD database. Based on current scientific knowledge, the variant is considered pathogenic (PVS1, PS2, PM2, PP3, PP5) according to the criteria of the American College of Medical Genetics and Genomics (ACMG). The mutation in the grin2b gene (p.Tyr1304Ter) was predicted to be deleterious through bioinformatics analysis tools. This study highlights the crucial role of the grin2b gene in normal brain development and communication within the nervous system. It also sheds light on the impact of a novel genetic mutation, identified through exome sequencing, on causing an intellectual developmental disorder in a child patient from Morocco.

New Biomarkers and Treatment Advances in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer lacking hormone receptor expression and HER2 gene amplification. TNBC represents a heterogeneous subtype of breast cancer, characterized by poor prognosis, high invasiveness, high metastatic potential, and a tendency to relapse. In this review, the specific molecular subtypes and pathological aspects of triple-negative breast cancer are illustrated, with particular attention to the biomarker characteristics of TNBC, namely: regulators of cell proliferation and migration and angiogenesis, apoptosis-regulating proteins, regulators of DNA damage response, immune checkpoints, and epigenetic modifications. This paper also focuses on omics approaches to exploring TNBC, such as genomics to identify cancer-specific mutations, epigenomics to identify altered epigenetic landscapes in cancer cells, and transcriptomics to explore differential mRNA and protein expression. Moreover, updated neoadjuvant treatments for TNBC are also mentioned, underlining the role of immunotherapy and novel and targeted agents in the treatment of TNBC.

Clinical Evidence of Circulating Tumor DNA Application in Aggressive Breast Cancer.

Breast cancer is clinically and biologically heterogeneous and is classified into different subtypes according to the molecular landscape of the tumor. Triple-negative breast cancer is a subtype associated with higher tumor aggressiveness, poor prognosis, and poor response to treatment. In metastatic breast cancer, approximately 6% to 10% of new breast cancer cases are initially staged IV (de novo metastatic disease). The number of metastatic recurrences is estimated to be 20-30% of all existing breast tumor cases, whereby the need to develop specific genetic markers to improve the prognosis of patients suffering from these deadly forms of breast cancer. As an alternative, liquid biopsy methods can minutely identify the molecular architecture of breast cancer, including aggressive forms, which provides new perspectives for more precise diagnosis and more effective therapeutics. This review aimed to summarize the current clinical evidence for the application of circulating tumor DNA in managing breast cancer by detailing the increased usefulness of this biomarker as a diagnostic, prognostic, monitoring, and surveillance marker for breast cancer.