Two novel compound heterozygous HOXB1 variants in congenital facial palsy: A case report and a brief review of the literature.

Hereditary congenital facial palsy (HCFP) is a medical condition caused by dysfunction of the seventh cranial nerve. HCFP is characterized by feeding difficulties and dysmorphic features in the orofacial region. In some cases hearing loss, strabismus, limb malformations, and musculoskeletal defects may be associated.

Identification of the DNA methylation signature of Mowat-Wilson syndrome.

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period.

Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals.

Purpose: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition.

Methods: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature.

Case Report: Sequential postzygotic mutation and gains of the paternal chromosome 11 carrying the mutated allele in a patient with epidermal nevus and rhabdomyosarcoma: evidence of a multiple-hit mechanism involving in oncogenic transformation.

We report a 7-year-old boy born with epidermal nevi (EN) arranged according to Blaschko's lines involving the face and head, right upper limb, chest, and left lower limb, who developed a left paratesticular embryonal rhabdomyosarcoma at 18 months of age. Parallel sequencing identified a gain-of-function variant (c.37G>C, p.

Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.

Background: KBG syndrome is caused by haploinsufficiency of and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined.

Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network.

Case report: Expanding the phenotype of -related intellectual disability syndrome and hyperkinetic movement disorder in differential diagnosis with epileptic seizures.

Objective: We aimed to report on previously unappreciated clinical features associated with -related intellectual disability (ID) syndrome, a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, and language delay, with or without autistic features.

Methods: We performed whole-exome sequencing (WES) to molecularly characterize an individual presenting with ID, epilepsy, autism spectrum disorder, behavioral problems, and facial dysmorphisms as major features.

Results: WES allowed us to identify a previously unreported splice site variant, c.

Developmental and epileptic encephalopathy in a young Italian woman with a de novo missense variant in the CLCN4 gene: A case report.

Introduction: Raynaud-Claes syndrome is a very rare X-linked condition, characterized by intellectual disability, impaired language development, brain abnormalities, facial dysmorphisms and drug-resistant epilepsy. It is caused by loss-of-function variants in the CLCN4 gene, which encodes the 2Cl-/H + exchanger ClC-4, prominently expressed in the hippocampus and cerebellum. Different genotypic variants have been described, each exhibiting specific phenotypic characteristics.

Prenatal Clinical Findings in -Related Capillary Malformation-Arteriovenous Malformation Syndrome.

Pathogenic variants in are typically associated with a clinical condition called "capillary malformation-arteriovenous malformation" (CM-AVM) syndrome, an autosomal dominant genetic disease characterized by a broad phenotypic variability, even within families. In CM-AVM syndrome, multifocal capillary and arteriovenous malformations are mainly localized in the central nervous system, spine and skin. Although CM-AVM syndrome has been widely described in the literature, only 21 cases with prenatal onset of clinical features have been reported thus far.

Characterization of BRCA Deficiency in Ovarian Cancer.

BRCA testing is recommended in all Ovarian Cancer (OC) patients, but the optimal approach is debated. The landscape of alterations was explored in 30 consecutive OC patients: 6 (20.0%) carried germline pathogenic variants, 1 (3.

Gingival Overgrowths Revealing Hamartoma Tumor Syndrome: Report of Novel Pathogenic Variants.

PTEN hamartoma tumor syndrome (PHTS), is a spectrum of disorders caused by mutations of PTEN, in which non-cancerous growths, called hamartomas, develop in different areas of the body, often including the oral mucosa. PHTS also implies a recognized increased risk of malignancies, as PTEN is a tumor suppressor gene capable of inhibiting progression of several cancers. One of the main and most common clinical manifestation of PHTS are gingival overgrowths presenting as warty lumps.

ANKLE2-related microcephaly: A variable microcephaly syndrome resembling Zika infection.

Objective: This study delineates the clinical and molecular spectrum of ANKLE2-related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus.

Methods: We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements.

MCPH1: A Novel Case Report and a Review of the Literature.

Microcephaly primary hereditary (MCPH) is a congenital disease characterized by nonsyndromic reduction in brain size due to impaired neurogenesis, often associated with a variable degree of intellectual disability (ID). The genetic etiology of MCPH is heterogeneous and comprises more than 20 loci, nearly all following a recessive inheritance pattern. The first causative gene identified, or , encodes a centrosomal protein that modulates chromosome condensation and cell cycle progression.

Posterior Lissencephaly Associated with Subcortical Band Heterotopia Due to a Variation in the Gene: A Case Report and Refining of the Phenotypic Spectrum.

Lissencephaly describes a group of conditions characterized by the absence of normal cerebral convolutions and abnormalities of cortical development. To date, at least 20 genes have been identified as involved in the pathogenesis of this condition. Variants in , encoding a protein involved in the regulation of neuronal migration, have been recently described as causative of lissencephaly with a posterior-prevalent involvement of the cerebral cortex and an autosomal dominant pattern of inheritance.

Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis.

Germline pathogenic variants cause a spectrum of disorders collectively labeled Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that is a "haploinsufficient" tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of -associated manifestations, with special focus on mucocutaneous manifestations.

Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples.

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.

Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?

The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.

Colorectal polyposis as a clue to the diagnosis of Cowden syndrome: Report of two cases and literature review.

Cowden Syndrome (CS) is an autosomal dominant disorder characterized by hamartomatous growth in several organs and by an increased risk of malignancies, which makes its recognition essential to undertake risk reduction measures. Although the involvement of gastrointestinal tract is extremely common, awareness of this entity among gastroenterologists appears limited. We report on two unrelated patients: a 46-year-old male and a 38-year-old woman, who were referred to the Genetic Clinic because of the endoscopic finding of multiple colorectal polyps.

Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos.

BRCA1 associated protein-1 (BAP1) germline mutations define a novel hereditary cancer syndrome, namely BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by an increased susceptibility to develop different cancer types, including mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and basal cell and squamous cell carcinoma. Currently, the role of BAP1 germline mutations in intrahepatic cholangiocarcinoma (iCCA) pathogenesis is less known. Here we report the first clinical case of a female patient who developed an iCCA when she was 47-years-old and was found to carry a novel germline mutation at a splicing site of exon 4 in BAP1 gene (NM_004656.

HDAC8 Loss of Function and SHOX Haploinsufficiency: Two Independent Genetic Defects Responsible for a Complex Phenotype.

We report a patient with developmental delay, brachydactyly type E, short stature, and tetralogy of Fallot. Brachydactyly-mental retardation syndrome (BDMR) was suspected based on the phenotype; however, array CGH excluded a 2q37 deletion, but identified a deletion encompassing the SHOX gene. BDMR is characterized by cognitive impairment, skeletal abnormalities involving hands and feet, short stature, and overweight.

Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help?

Detection of variants of uncertain significance (VUSs) in BRCA1 and BRCA2 genes poses relevant challenges for counseling and managing patients. VUS carriers should be managed similarly to probands with no BRCA1/2 variants detected, and predictive genetic testing in relatives is discouraged. However, miscomprehension of VUSs is common and can lead to inaccurate risk perception and biased decisions about prophylactic surgery.

Infectious meningitis/encephalitis: evaluation of a rapid and fully automated multiplex PCR in the microbiological diagnostic workup.

Infectious diseases of the central nervous system (CNS) such as meningitis/encephalitis (ME) require rapid identification of causative pathogens for effective treatment. This study evaluated the analytical performance and clinical utility of a fully automated multiplex PCR test to improve the microbiological diagnostic workup of ME. Seventy-seven cerebrospinal fluid (CSF) samples from 77 patients with suspected ME were studied.

Somatic APC mosaicism and oligogenic inheritance in genetically unsolved colorectal adenomatous polyposis patients.

Germline variants in the APC gene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3 genes and somatic APC mosaicism have been reported as alternative causes of polyposis. However, ~30-50% of cases of polyposis remain genetically unsolved.