Role of Cytoskeletal Diaphanous-Related Formins in Hearing Loss.

Hearing relies on the proper functioning of auditory hair cells and on actin-based cytoskeletal structures. Diaphanous-related formins (DRFs) are evolutionarily conserved cytoskeletal proteins that regulate the nucleation of linear unbranched actin filaments. They play key roles during metazoan development, and they seem particularly pivotal for the correct physiology of the reproductive and auditory systems.

Heterozygous COL4A3/COL4A4 mutations: the hidden part of the iceberg?

Background: Single mutations in COL4A3/COL4A4 genes have been described in patients with autosomal dominant Alport syndrome and thin basement membrane nephropathy, without a shared definition of these patients within the medical community. We aimed to better categorize this clinical entity by examining clinical manifestations, family history, pathological features and genetics.

Methods: We retrospectively analyzed patients with causative heterozygous COL4A3/COL4A4 mutations referred to us between 1990 and 2019.

Gene in Hereditary Non-syndromic Hearing Loss: Recurrence and Incomplete Penetrance of the p.C113Y Mutation in Northwest Africa.

Inherited hearing loss is extremely heterogeneous both clinically and genetically. In addition, the spectrum of deafness-causing genetic variants differs greatly among geographical areas and ethnicities. The identification of the causal mutation in affected families allows early diagnosis, clinical follow-up, and genetic counseling.

X-Linked Alport Syndrome in Women: Genotype and Clinical Course in 24 Cases.

X-linked Alport syndrome (XLAS) females are at risk of developing proteinuria and chronic kidney damage (CKD). The aim of this study is to evaluate the genotype-phenotype correlation in this rare population. This is a prospective, observational study of XLAS females, confirmed by a pathogenic mutation in and renal ultrastructural evaluation.

Audiovestibular Phenotypes and Advanced Magnetic Resonance Imaging Features of Cochlin Gene Mutation Carriers.

Objective: To describe clinical and imaging findings in a group of patients affected by nonsyndromic deafness A9 (DFNA9), using advanced magnetic resonance imaging (MRI) with 3-dimensional (3D) fluid-attenuated inversion recovery (FLAIR) sequence.

Method: A retrospective case review was conducted in a tertiary referral center in Italy. Four sequential adult DFNA9-affected patients, who had undergone MRI at our Department between January 2017 and June 2018, were enrolled (male = 2, female = 2; median age: 65.

Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss.

Hereditary hearing loss (HHL) and age-related hearing loss (ARHL) are two major sensory diseases affecting millions of people worldwide. Despite many efforts, additional HHL-genes and ARHL genetic risk factors still need to be identified. To fill this gap a large genomic screening based on next-generation sequencing technologies was performed.

Alport syndrome cold cases: Missing mutations identified by exome sequencing and functional analysis.

Alport syndrome (AS) is an inherited progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes. Despite simultaneous screening of these genes being widely available, mutation detection still remains incomplete in a non-marginal portion of patients. Here, we applied whole-exome sequencing (WES) in 3 Italian families negative after candidate-gene analyses.

First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.

Perrault syndrome (MIM #233400) is a rare autosomal recessive disorder characterized by ovarian dysgenesis and primary ovarian insufficiency in females, and progressive hearing loss in both genders. Recently, mutations in five genes (HSD17B4, HARS2, CLPP, LARS2 and C10ORF2) were found to be responsible for Perrault syndrome, although they do not account for all cases of this genetically heterogeneous condition. We used whole-exome sequencing to identify pathogenic variants responsible for Perrault syndrome in an Italian pedigree with two affected siblings.

Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome.

Background: Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC-HUS) is a severe acute illness without specific treatment except supportive care; fluid management is concentrated on preventing fluid overload for patients, who are often oligoanuric. Hemoconcentration at onset is associated with more severe disease, but the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset have not been explored.

Methods: All the children with STEC-HUS referred to our center between 2012 and 2014 received intravenous infusion targeted at inducing an early volume expansion (+10% of working weight) to restore circulating volume and reduce ischemic or hypoxic tissue damage.

The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy.

Next-generation sequencing is currently the technology of choice for gene/mutation discovery in genetically-heterogeneous disorders, such as inherited sensorineural hearing loss (HL). Whole-exome sequencing of a single Italian proband affected by non-syndromic HL identified a novel missense variant within the PRPS1 gene (NM_002764.3:c.

Hemoconcentration: a major risk factor for neurological involvement in hemolytic uremic syndrome.

Background: Shigatoxin-associated hemolytic uremic syndrome (STEC-HUS) is a common thrombotic microangiopathy (TMA) in which central nervous system (CNS) involvement is responsible for the majority of deaths and for severe long-term sequelae. We have analyzed the role of hemoconcentration in disease severity.

Methods: This was a retrospective review of the records and laboratory data at presentation of all patients with STEC-HUS cases (n = 61) over a 10-year period.

Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.

Alterations of USH2A, encoding usherin, are responsible for more than 70% of cases of Usher syndrome type II (USH2), a recessive disorder that combines moderate to severe hearing loss and retinal degeneration. The longest USH2A transcript encodes usherin isoform b, a 5,202-amino-acid transmembrane protein with an exceptionally large extracellular domain consisting notably of a Laminin N-terminal domain and numerous Laminin EGF-like (LE) and Fibronectin type III (FN3) repeats. Mutations of USH2A are scattered throughout the gene and mostly private.

The genetics of the alternative pathway of complement in the pathogenesis of HELLP syndrome.

Objective: Recent preliminary evidence suggests that gene mutations in the alternative pathway of complement may play a crucial role in the pathogenesis of HELLP syndrome. To verify this hypothesis, a consecutive series of women who developed the syndrome was screened for variants in alternative pathway genes.

Methods: The coding sequences and intron-exon boundaries of the complement factor H (CFH), complement factor I (CFI), Membrane Cofactor Protein (MCP), complement factor B (CFB) and C3 were sequenced in 33 women with a diagnosis of HELLP syndrome.

Molecular and functional studies of 4 candidate loci in Pendred syndrome and nonsyndromic hearing loss.

Patients with PS or non-syndromic deafness were submitted to genetic/functional analyzes of SLC26A4, of its binding domain for FOXI1 (FOXI1-DBD), of the transcription activator FOXI1, and of the potassium channel KCNJ10. SLC26A4 was the most frequently mutated gene. An altered intracellular localization with immunocytochemistry, and a hampered maturation process were demonstrated for two novel SLC26A4 variants.

A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing.

The miR-96, miR-182 and miR-183 microRNA (miRNA) family is essential for differentiation and function of the vertebrate inner ear. Recently, point mutations within the seed region of miR-96 were reported in two Spanish families with autosomal dominant non-syndromic sensorineural hearing loss (NSHL) and in a mouse model of NSHL. We screened 882 NSHL patients and 836 normal-hearing Italian controls and identified one putative novel mutation within the miR-96 gene in a family with autosomal dominant NSHL.

GJB2 and MTRNR1 contributions in children with hearing impairment from Northern Cameroon.

Objective: the aim of this work was to evaluate the possible different impacts of genetic and environmental factors in childhood deafness in northern Cameroon. GJB2 mutations are responsible for more than half of all cases of prelingual nonsyndromic recessive deafness in Caucasians, representing the most important deafness-causing factor in the industrialized world. Other genes such as MTRNR1 are also involved.

Triple X syndrome: characteristics of 42 Italian girls and parental emotional response to prenatal diagnosis.

We report clinical and behavioural evaluation data in 42 Italian girls with triple X syndrome whose diagnosis was made prenatally between 1998 and 2006 in three Italian centres. At initial evaluation, reproductive and medical histories were collected. Clinical assessment of the child was performed by a clinical geneticist and included a detailed personal history, physical evaluation and auxological measurements.

Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies.

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin.

Analysis of the GJB2 and GJB6 genes in Italian patients with nonsyndromic hearing loss: frequencies, novel mutations, genotypes, and degree of hearing loss.

Mutations in the GJB2 gene, which encodes the gap-junction protein connexin 26, are the most common cause of nonsyndromic hearing loss (NSHL) and account for about 32% of cases. We analyzed 734 patients and identified mutations in 474/1468 chromosomes. Thirty-six different mutations and five polymorphisms were found in 269 NSHL subjects.

Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene.

Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype-phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound.

A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy.

Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene.

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein.

Objective: Pendred syndrome (PS) is characterized by the association of sensorineural hearing loss (SNHL) and a partial iodide organification defect at the thyroid level. It is caused by mutations in the SLC26A4 gene. The encoded transmembrane protein, called pendrin, has been found to be able to transport chloride and other anions.

A new de novo missense mutation in connexin 26 in a sporadic case of nonsyndromic deafness.

Objectives: Mutations in the GJB2 gene, encoding Connexin 26, can cause nonsyndromic recessive deafness or dominant hearing loss (HL) with or without keratoderma. The objective was to perform a molecular evaluation to establish the inherited pattern of deafness in the sporadic cases afferent to our center.

Methods: The subject was a 2-year-old Italian girl with nonsyndromic early onset HL.