Search Results (22)

Hearing loss (HL) is a common sensory disorder, with syndromic forms accounting for ~30% of genetic cases. Due to phenotypic and genetic heterogeneity, accurate diagnosis remains challenging. Exome sequencing (ES) offers a powerful tool to uncover the underlying genetic causes. This study aimed to investigate the genetic basis of syndromic hearing loss (SHL) in North African Moroccan patients through ES. Seven individuals with suspected SHL were recruited from Hassan II University Hospital, Fez. After clinical and audiological assessments, ES was performed to identify causal genetic variants. Two of the participating individuals had Usher syndrome, and one each had Cornelia de Lange syndrome, Wolfram syndrome, Jervell and Lange-Nielsen syndrome, CHARGE syndrome, and Waardenburg syndrome. The causes of all these syndromes were determined, with pathogenic variants in MYO7A, USH1G, SMC1A, WFS1, KCNQ1, CHD7, and MITF. Across the combined cohort of reported Moroccan SHL cases, variants in CHD7 and MYO7A were among the most frequently observed, while USH1G and MITF variants were rare. This study enhances the understanding of SHL in North Africa, revealing a high level of locus and allelic heterogeneity. Examining disparate populations yields novel insights into the etiology of SHL, which can subsequently enhance genetic diagnosis and tailored management strategies. Full article

Paired box (PAX) genes encode a family of nine transcription factors that function as master regulators of embryogenesis, organogenesis, and lineage specification. Their tightly regulated spatial and temporal expression is essential for the development of multiple organ systems, including the central nervous system, eyes, kidneys, immune system, musculoskeletal system, and endocrine organs. Germline mutations of PAX genes result in a broad and often pleiotropic spectrum of human disease, reflecting the developmental programs governed by each family member. Pathogenic variants in PAX genes underlie diverse congenital disorders such as aniridia (PAX6), renal coloboma syndrome (PAX2), otofaciocervical syndrome with immunodeficiency (PAX1), Waardenburg syndrome (PAX3), maturity-onset diabetes of the young (PAX4), and tooth agenesis (PAX9). These conditions frequently demonstrate variable expressivity, incomplete penetrance, and overlapping phenotypes, which make it challenging to be clinically recognized. Beyond embryogenesis and embryologic development, emerging evidence indicates that several PAX proteins remain active in postnatal tissue maintenance, adult stem cell regulation, immune function, and regenerative responses (particularly PAX7 in skeletal muscle satellite cells and PAX5 in B-cell homeostasis), further expanding their clinical relevance. This review provides a synopsis of the major, clinically relevant, germline PAX gene mutations, emphasizing genotype–phenotype correlations, developmental mechanisms, and disease classification across the organ systems. By integrating molecular genetics with human pathology, we highlight the diagnostic implications of PAX genes as central determinants of congenital disease and provide a framework for understanding how alterations in the developmental transcriptional networks translate into human pathology. Full article

Waardenburg syndrome (WS) represents a group of genetic conditions characterized by auditory and pigmentation defects. Pathogenic variants in PAX3, MITF, SOX10, EDN3, EDNRB, SNAI2, and KITLG genes have been associated with WS across multiple populations; a comprehensive study of WS in Africa has not yet been reported. We conducted a systematic review of clinical expressions and genetics of WS across Africa. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed, and the study protocol was registered on PROSPERO, the International Prospective Register of Systematic Reviews (2025 CRD420250655744). A literature search was performed on Google Scholar, PubMed, Scopus, Directory of Open Access Journals (DOAJ), Global Index Medicus, African-Wide Information, ScienceDirect, Connecting Repositories (CORE), and the Web of Science databases. We reviewed a total of 15 articles describing 84 WS cases, which showed no gender bias and a mean age at reporting of 17.5 years. Congenital, sensorineural, and profound hearing loss was described in most cases (66.7%; n = 56/84). WS type 2 (WS2), with characteristically no dystopia canthorum, is the predominant subtype (36.9%; n = 31/84). Pathogenic variants in four WS known genes, i.e., PAX3 (13 families), SOX10 (7 families), EDNRB (4 families), and EDN3 (1 family), were reported in Morocco, Tunisia, and South Africa. One candidate gene (PAX8) was described in one family in Ghana. Two non-syndromic hearing loss (NSHL) genes (BDP1 and MYO6) were reported in two separate families in South Africa, suggesting a possible phenotypic expansion. The highest number of WS cases was described in South Africa (38.1%; n = 32/84) and Tunisia (26.2%; n = 22/84). Gene variants were missense (27/43), deletion (7/43), splicing (5/43), nonsense (2/43), indel (1/43), and duplication (1/43), chiefly segregating in an autosomal dominant inheritance mode. There was no functional data to support the pathogenicity of putative causative variants. This review showed that WS2 is the most common in Africa. Variants in PAX3 and SOX10 were the predominant genetic causes. This study emphasizes the need to further investigate in-depth clinical characterization, molecular landscape, and the pathobiology of WS in Africa. Full article

Background/Objectives: Cutaneous hypopigmentation is a common clinical sign observed in a variety of disorders. It may be congenital or acquired, localized or diffuse, and can range from benign to being associated with systemic conditions, including those affecting the central nervous system. Recognition of the key clinical features associated with each disorder is essential for accurate diagnosis and for differentiating one condition from another. Methods: PubMed, Embase, and Scopus databases were used to prepare a systematic review. Search terms were: “congenital”, “cutaneous”, “localized”, “diffuse”, “hypopigmentation” and “neurological disorders/signs”. The focus was on congenital cutaneous hypopigmentation, distinguishing between localized and diffuse presentations, with emphasis on neurological involvement. Peer-reviewed articles, case series, and original studies with neurological manifestations of the disease were reviewed. Cutaneous hypopigmentation disorders associated with diffuse cerebral involvement include syndromes such as Chediak–Higashi, Griscelli, Elejalde, Cross, Tietz albinism-deafness, Prader–Willi, Angelman, and several congenital metabolic disorders. In contrast, the ‘localized’ group comprises syndromes such as Waardenburg, Incontinentia pigmenti, and the phacomatoses, including hypomelanosis of Ito and tuberous sclerosis complex. Results: Overlapping phenotypes and genetic heterogeneity lead to diagnostic challenges and potential errors suggesting multiple specialists. The main clinical features of each disorder are discussed, with particular attention paid to neurological signs. A practical flowchart is provided to help distinguish between ‘diffuse’ and ‘localized’ forms with neurological involvement. Conclusions: Early identification of cutaneous features, followed by comprehensive clinical and instrumental evaluation, enables timely and accurate diagnosis, ultimately improving the clinical outcomes for affected children. Full article

Background/Objectives: Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss (SNHL) and pigmentation anomalies. While hearing impairment is a well-established feature of WS, vestibular dysfunction is also reported. This study aimed to investigate vestibular deficits in pediatric WS patients with SNHL, correlating these findings with molecular, audiometric, and radiological data to establish distinct phenotypic profiles for each WS subtype and associated pathogenic variants. Methods: This retrospective study included children with a genetically confirmed diagnosis of WS who underwent vestibular, auditory, and inner ear radiological assessments as part of their routine medical care between July 2000 and May 2022. Data were collected from medical records, including medical history, clinical findings, and assessment results. Results: Vestibular dysfunction was found to be highly prevalent, affecting 64% of the cohort, often impacting the canal sensory organ (89%) and occasionally the otolithic function (33%). Patients with SOX10 pathogenic variations exhibited a markedly higher risk of vestibular dysfunction, highlighting the unique role of SOX10 in inner ear development. Notably, inner ear malformations were identified in all SOX10-mutated subjects, whereas such anomalies were rare among individuals with other WS gene variants, occurring in only two additional cases with minor malformations. Conclusions: This study reveals a significant prevalence of vestibular deficits in pediatric WS patients with SNHL, emphasizing the need for routine vestibular assessments. The higher prevalence and severity of vestibular impairments in SOX10-mutated patients underscore the importance of molecular analysis in clinical diagnosis and management. Full article

Paired box gene 3 (PAX3) plays an important role in craniofacial development. Mutations in this gene are associated with Waardenburg syndrome, which is a condition characterized by facial anomalies such as widely spaced inner corners of the eyes. PAX3 gene polymorphisms are associated with the relative position of the nasal root (nasion), even among healthy individuals. Facial morphology has primarily been examined using three-dimensional (3D) facial scans of soft tissues, whereas studies focusing on hard tissues remain limited. Therefore, the present study aimed to analyze 3D craniofacial morphology in hard tissues using computed tomography imaging and investigate the influence of PAX3 polymorphisms on the 3D morphology of the nasal root. The analysis was conducted on three populations: 201 healthy Japanese, 74 healthy Korean, and 142 healthy Egyptian individuals. DNA was extracted from saliva samples, and the genotypes of two PAX3 single-nucleotide polymorphisms (SNPs; rs9288572 and rs7559271) were analyzed. A multiple regression analysis of the association between these SNPs and measurements related to nasal root morphology revealed a significant association between rs7559271 and the protrusion angle of the nasion. These findings suggest that PAX3 gene polymorphisms influence the morphological development of the nasal root within the normal range of hard tissues. Full article

Waardenburg syndrome (WS) is a rare genetic disorder that affects both hearing and pigmentation. The wide divergence of WS poses significant diagnostic and management challenges. This study investigated type 4 WS within an underrepresented Mongolian population. Whole-exome sequencing revealed that two unique heterozygous variants were identified in the SOX10 gene: c.393C>G (p.Asn131Lys) in a five-year-old female patient presenting with profound sensorineural hearing loss (SNHL), dystopia canthorum, and a white forelock; and c.535A>T (p.Lys179Ter) in a nine-year-old male patient presenting with profound SNHL, dystopia canthorum, and Hirschsprung’s disease. Temporal bone imaging revealed abnormalities in the inner ear structure in both patients. The genotypic and phenotypic characteristics were meticulously delineated, incorporating the deleterious effects of these variants, as evaluated by multiple predictive tools and the American College of Medical Genetics and Genomics (ACMG) criteria. In addition, structural characterizations were also presented using AlphaFold. The findings of this study contribute valuable genetic data to the limited literature on type 4 WS within this ethnic group and highlight the importance of genetic testing and multidisciplinary care for this rare disorder in settings with limited resources. Full article

Background: Over three-quarters of the people living with hearing impairment (HI) live in low- and middle-income countries. However, Rwanda has limited data on the clinical profile of HI. Aim: We used community-based nationwide recruitment of participants to determine the etiology of early-onset (<7 years of age) HI in Rwanda. Methods: Participants were included after clinical examination, including audiological assessment by pure tone audiometry and/or auditory brainstem response. DNA was extracted from peripheral blood, and the entire coding region of GJB2 was interrogated using Sanger sequencing. Multiplex PCR and Sanger sequencing were used to analyze the prevalence of the GJB6-D3S1830 deletion. Results: The participants were recruited from seven inclusive schools, one university teaching hospital, and four independent communities nationwide. We reviewed the clinical histories of 422 individuals affected by early-onset HI from 348 families and found that 21.18% (n = 89/422) was linked to early childhood meningitis infection while 51.23% (n = 216/422) was categorized as unknown HI etiology. Because of putative genetic causes, 82/348 (23.6%) families were reviewed and identified for genetic testing. Within the 82 families with potential genetic causes, 122 individuals were affected by HI, and 205 were unaffected. The male/female ratio of those enrolled for genetic investigations was 0.79 (n = 145/182). The mean age of diagnosis of HI was 4.3 ± 2.6 years. Most cases (89.36%, n = 109/122) reviewed were prelingual. Pedigree analysis suggested autosomal recessive inheritance in 46.3% (n = 38/82) of families. Most HI participants from familial cases had nonsyndromic HI (94.2%, n = 115/122). Waardenburg syndrome was found in three participants out of seven participants who presented with syndromic HI, while three other participants manifested signs of Usher syndrome and one with suspected Noonan syndrome. Molecular analysis did not find pathogenic variants in GJB2 or GJB6-D3S1830 deletion in any of the probands tested (n = 27/122; 22.13%) or 100 non-affected control participants. Conclusions: This study revealed an overall late diagnosis (mean at 4.3 years) of HI in Rwanda. Most cases were of unknown origin or putative environmental origin (76.4%), with meningitis predominating as the acquired cause of early-onset HI. Among cases of putative genetic etiology, nonsyndromic HI accounted for the large majority (94.2%). However, GJB2 and GJB6 pathogenic variants were not identified in the screened proportion of the cohort. This study calls for the implementation of neonatal hearing screening as well as reinforcement of immunization programs to reduce the burden of acquired early-onset HI in Rwanda. Additional genomic studies, ideally using exome sequencing for familial cases, are needed. Full article

Waardenburg syndrome (WS) is a common genetic cause of syndromic hearing loss, accounting for 2–5% of congenital cases. It is characterized by hearing impairment and pigmentation abnormalities in the skin, hair, and eyes. Seven genes are associated with WS: PAX3, MITF, EDNRB, EDN3, SOX10, KITLG, and SNAI2. This study investigates the genetic causes of WS in three familial cases. Whole-exome sequencing (WES) was performed to identify single nucleotide variants (SNVs). Copy number variants (CNVs) were analyzed from the WES raw data and through multiplex ligation-dependent probe amplification (MLPA). The study identified one pathogenic SNV and two novel CNVs, corresponding to type I and type II WS patterns in the three families. The SNV, a nonsense variant (c.1198C>T p.Arg400*), was found in MITF and segregated in the affected father. The two CNVs were a deletion of exon 5 in PAX3 in a family with two affected members and a large novel deletion comprising seven genes, including SOX10, in a family with three affected members. These findings confirmed a WS diagnosis through genetic testing. The study emphasizes the importance of integrating multiple genetic testing approaches for accurate and reliable diagnosis, highlighting their role in improving patient management and providing tailored genetic counseling. Full article

During the last twenty years, minimal white spotting associated with blue eyes was selected by feline breeders to create the Altai, Topaz, and Celestial breeds. Additionally, certain breeders introduced this trait in their lineages of purebred cats. The trait has been called “dominant blue eyes (DBE)” and was confirmed to be autosomal dominant in all lineages. DBE was initially described in outbred cats from Kazakhstan and Russia and in two purebred lineages of British cats from Russia, as well as in Dutch Maine Coon cats, suggesting different founding effects. We have previously identified two variants in the Paired Box 3 (PAX3) gene associated with DBE in Maine Coon and Celestial cats; however, the presence of an underlying variant remains undetermined in other DBE breeding lines. Using a genome-wide association study, we identified a single region on chromosome C1 that was associated with DBE in British cats. Within that region, we identified PAX3 as the strongest candidate gene. Whole-genome sequencing of a DBE cat revealed an RD-114 retrovirus LTR (long terminal repeat) insertion within PAX3 intron 4 (namely NC_018730.3:g.206975776_206975777insN[433]) known to contain regulatory sequences. Using a panel of 117 DBE cats, we showed that this variant was fully associated with DBE in two British lineages, in Altai cats, and in some other DBE lineages. We propose that this NC_018730.3:g.206975776_206975777insN[433] variant represents the DBE^ALT (Altai Dominant Blue Eye) allele in the domestic cat. Finally, we genotyped DBE cats from 14 lineages for the three PAX3 variants and showed that they were not present in four lineages, confirming genetic heterogeneity of the DBE trait in the domestic cat. Full article

Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo epithelial–mesenchymal transition (EMT) and upon key developmental gene deregulation, fetuses and neonates are prone to exhibit diverse manifestations depending on the affected area. These conditions are generally rare and often have a genetic basis, with many following Mendelian inheritance patterns, thus making them perfect candidates for precision medicine. Examples include cranial NCPs, like Goldenhar syndrome and Axenfeld–Rieger syndrome; cardiac–vagal NCPs, such as DiGeorge syndrome; truncal NCPs, like congenital central hypoventilation syndrome and Waardenburg syndrome; and enteric NCPs, such as Hirschsprung disease. Additionally, NCCs’ migratory and differentiating nature makes their derivatives prone to tumors, with various cancer types categorized based on their NCC origin. Representative examples include schwannomas and pheochromocytomas. This review summarizes current knowledge of diseases arising from defects in NCCs’ specification and highlights the potential of precision medicine to remedy a clinical phenotype by targeting the genotype, particularly important given that those affected are primarily infants and young children. Full article

Waardenburg syndrome (WS) is characterized by hearing loss and pigmentary abnormalities of the eyes, hair, and skin. The condition is genetically heterogeneous, and is classified into four clinical types differentiated by the presence of dystopia canthorum in type 1 and its absence in type 2. Additionally, limb musculoskeletal abnormalities and Hirschsprung disease differentiate types 3 and 4, respectively. Genes PAX3, MITF, SOX10, KITLG, EDNRB, and EDN3 are already known to be associated with WS. In WS, a certain degree of molecularly undetected patients remains, especially in type 2. This study aims to pinpoint causative variants using different NGS approaches in a cohort of 26 Brazilian probands with possible/probable diagnosis of WS1 (8) or WS2 (18). DNA from the patients was first analyzed by exome sequencing. Seven of these families were submitted to trio analysis. For inconclusive cases, we applied a targeted NGS panel targeting WS/neurocristopathies genes. Causative variants were detected in 20 of the 26 probands analyzed, these being five in PAX3, eight in MITF, two in SOX10, four in EDNRB, and one in ACTG1 (type 2 Baraitser-Winter syndrome, BWS2). In conclusion, in our cohort of patients, the detection rate of the causative variant was 77%, confirming the superior detection power of NGS in genetically heterogeneous diseases. Full article

The embryonic development of neural crest cells and subsequent tissue differentiation are intricately regulated by specific transcription factors. Among these, SOX10, a member of the SOX gene family, stands out. Located on chromosome 22q13, the SOX10 gene encodes a transcription factor crucial for the differentiation, migration, and maintenance of tissues derived from neural crest cells. It plays a pivotal role in developing various tissues, including the central and peripheral nervous systems, melanocytes, chondrocytes, and odontoblasts. Mutations in SOX10 have been associated with congenital disorders such as Waardenburg–Shah Syndrome, PCWH syndrome, and Kallman syndrome, underscoring its clinical significance. Furthermore, SOX10 is implicated in neural and neuroectodermal tumors, such as melanoma, malignant peripheral nerve sheath tumors (MPNSTs), and schwannomas, influencing processes like proliferation, migration, and differentiation. In mesenchymal tumors, SOX10 expression serves as a valuable marker for distinguishing between different tumor types. Additionally, SOX10 has been identified in various epithelial neoplasms, including breast, ovarian, salivary gland, nasopharyngeal, and bladder cancers, presenting itself as a potential diagnostic and prognostic marker. However, despite these associations, further research is imperative to elucidate its precise role in these malignancies. Full article

This study examines the last 10 years of medical literature on the benefits of cochlear implantation in children who are deaf or hard of hearing (DHH) with additional disabilities. The most recent literature concerning cochlear implants (CIs) in DHH children with additional disabilities was systematically explored through PubMed, Embase, Scopus, PsycINFO, and Web of Science from January 2012 to July 2023. Our two-stage search strategy selected a total of 61 articles concerning CI implantation in children with several forms of additional disabilities: autism spectrum disorder, cerebral palsy, visual impairment, motor disorders, developmental delay, genetic syndromes, and intellectual disability. Overall, many children with additional disabilities benefit from CIs by acquiring greater environmental sound awareness. This, in turn, improves non-verbal communication and adaptive skills, with greater possibilities to relate to others and to be connected with the environment. Instead, despite some improvement, expressive language tends to develop more slowly and to a lesser extent compared to children affected by hearing loss only. Further studies are needed to better appreciate the specificities of each single disability and to personalize interventions, not restricting the analysis to auditory and language skills, but rather applying or developing cross-culturally validated instruments able to reliably assess the developmental trajectory and the quality of life of DHH children with additional disabilities before and after CI. Full article

Mutations in the mouse microphthalmia-associated transcription factor (Mitf) gene affect retinal pigment epithelium (RPE) differentiation and development and can lead to hypopigmentation, microphthalmia, deafness, and blindness. For instance, an association has been established between loss-of-function mutations in the mouse Mitf gene and a variety of human retinal diseases, including Waardenburg type 2 and Tietz syndromes. Although there is evidence showing that mice with the homozygous Mitf^mi mutation manifest microphthalmia and osteopetrosis, there are limited or no data on the effects of the heterozygous condition in the eye. Mitf mice can therefore be regarded as an important model system for the study of human disease. Thus, we characterized Mitf^mi/+ mice at 1, 3, 12, and 18 months old in comparison with age-matched wild-type mice. The light- and dark-adapted electroretinogram (ERG) recordings showed progressive cone-rod dystrophy in Mitf^mi/+ mice. The RPE response was reduced in the mutant in all age groups studied. Progressive loss of pigmentation was found in Mitf^mi/+ mice. Histological retinal sections revealed evidence of retinal degeneration in Mitf^mi/+ mice at older ages. For the first time, we report a mouse model of progressive cone-rod dystrophy and RPE dysfunction with a mutation in the Mitf gene. Full article