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Review

Otofaciocervical Syndrome and Its Overlap with Branchiootorenal Spectrum: An Integrated Literature Analysis of EYA1-Related Disorders, Including a Novel Case with an 8q13.2q13.3 Deletion

by
Ludovico Graziani
1,2,*,†,
Miriam Lucia Carriero
1,†,
Salvatore Melchionda
3,
Bartolomeo Augello
3,
Orazio Palumbo
3,
Mario Bengala
1,4,
Marco Castori
3 and
Giuseppe Novelli
1,4
1
Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, 00133 Rome, Italy
2
Genetics and Developmental Biology Unit, Azienda Ospedaliera Universitaria Sassari, 07100 Sassari, Italy
3
UOC Genetica Medica, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
4
Medical Genetics Unit, “Tor Vergata” University Hospital, 00133 Rome, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Genes 2025, 16(11), 1267; https://doi.org/10.3390/genes16111267
Submission received: 29 August 2025 / Revised: 26 September 2025 / Accepted: 14 October 2025 / Published: 28 October 2025
(This article belongs to the Special Issue Molecular Genetics of Rare Disorders)
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Abstract

Otofaciocervical syndrome (OTFCS) is a rare disorder characterized by facial, auditory, and shoulder girdle anomalies. Its significant phenotypic overlap with branchiootorenal spectrum disorders (BORSD)—both linked to EYA1 (EYA transcriptional coactivator and phosphatase 1) gene defects—has raised questions about whether they are distinct entities or part of a single clinical spectrum. We report a novel OTFCS patient with a de novo microdeletion spanning EYA1 and review all published cases of EYA1-related disorders. Our analysis reveals that all EYA1 variant types (truncating, missense, CNV, etc.) can cause BORSD, OTFCS, or hybrid phenotypes, firmly supporting their status as allelic disorders. Crucially, all reported OTFCS patients with EYA1 variants had renal anomalies, a feature previously considered a hallmark of BORSD. We conclude that BORSD and OTFCS constitute a single EYA1-related diagnostic continuum. This reclassification mandates the development of follow-up protocols that integrate renal, otologic, and skeletal surveillance in EYA1-related disorders, including OTFCS, and refines prognostic and genetic counseling.

1. Introduction

Craniofacial syndromes associated with branchial arch anomalies represent a clinically and genetically heterogeneous group of disorders, often characterized by overlapping features that complicate diagnosis and etiological classification [1,2]. Among these, Otofaciocervical syndrome (OTFCS) is a rare genetic disorder first described by Fara et al. in 1967, with fewer than ten cases reported in the literature [3,4]. It is characterized by peculiar craniofacial traits (e.g., long triangular face, broad forehead, narrow nose and mandible, and high arched palate), ear abnormalities (e.g., low-set, cup-shaped ears with prominent conchae and a hypoplastic tragus and lobe) often associated with hearing loss, and shoulder girdle anomalies (sloping shoulders, low-set clavicles, winged scapulae, and trapezius hypoplasia). Skeletal anomalies other than girdle anomalies and nasolacrimal duct defects are frequently reported, whereas neurodevelopmental delay and short stature are observed only in some patients [5,6]. OTFCS shares significant phenotypic overlap with branchiootorenal spectrum disorders (BORSD) [7,8]. Nonetheless, they have been previously described as clinically distinct entities: phenotypic traits such as facial dysmorphisms and shoulder girdle anomalies were considered specific to OTFCS, whereas BORSD were explicitly characterized by functional and structural renal anomalies (Table 1) [9,10].
Heterozygous variants in EYA1 (EYA transcriptional coactivator and phosphatase 1) account for approximately 40–75% of individuals clinically diagnosed with BORSD [11,12], but have also been reported in OTFCS patients [13,14,15]. Other genes in the Pax-Six-Eya-Dach network (PSEDN) are likewise implicated in both phenotypes. Heterozygous variants in SIX1 (sine oculis homeobox homolog 1) and SIX5 (sine oculis homeobox homolog 5) have been detected in 3.0–45% and 0–3.1% of individuals with BORSD, respectively [16,17,18]. In addition, biallelic PAX1 (paired box 1) variants underlie OTFCS type 2 with T-cell deficiency (OTFCS2) [19,20,21,22], while loss-of-function (LoF) variants in EYA4 (EYA transcriptional coactivator and phosphatase 4) have more recently been reported in a single affected family [4].
Whether OTFCS and BORSD represent distinct nosological entities or instead form part of a broader phenotypic continuum remains unresolved, as the precise genetic basis of OTFCS is not yet fully clarified. Importantly, some individuals with a BORSD diagnosis present with features typical of OTFCS—musculoskeletal and neurodevelopmental involvement—while some OTFCS patients exhibit renal anomalies, suggesting that the two conditions may, at least in part, represent allelic disorders [11,23,24]. This growing body of evidence supports the hypothesis that these disorders may, at least in part, represent allelic conditions.
In this study, we report a novel patient presenting with OTFCS harboring a de novo microdeletion encompassing EYA1 and perform a comprehensive review of all published cases of EYA1-related disorders. By delineating overlaps and distinctions between OTFCS and BORSD, we aim to refine their allelic relationship, improve diagnostic precision, and inform genetic counseling, while contributing to a deeper understanding of the molecular mechanisms underlying these syndromes.

2. Materials and Methods

2.1. Clinical and Molecular Data

Clinical and audiological information was collected for the index patient, including detailed phenotypic characterization with particular attention to branchial, auricular, renal, and neurodevelopmental features. Audiological assessments included the type and degree of hearing loss. Genomic DNA was extracted from peripheral blood samples.
Chromosome microarray analysis (CMA) was performed using the CytoScan XON array (Thermo Fisher Scientific, Waltham, MA, USA).
Multiplex Ligation-dependent Probe Amplification (MLPA) was performed using the SALSA MLPA probemix P153-B1 EYA1 kit (MRC-Holland, Amsterdam, The Netherlands), and variant analysis was carried out with Coffalyser.Net software v.240129.1959 (MRC-Holland, Amterdam, The Netherlands). The coordinates of detected deletions were mapped to the human genome assembly hg38 (GRCh38). Segregation analysis was performed to determine the inheritance pattern.

2.2. Literature Review and Data Extraction

A systematic literature review was conducted (last search: August 2025) using PubMed, Scopus, Embase, and Google Scholar, with the following keywords: “BORSD”, “BOR syndrome”, “BO syndrome”, “OFC syndrome”, “OTFC syndrome”, “BOF syndrome”, “BOU syndrome”, “branchio-oto-renal”, “branchio-otic”, “Otofaciocervical”, “del”, “deletion”, and “EYA1”. Filters applied: English language, human studies, and original clinical/genetic data.

2.3. Inclusion and Exclusion Criteria

Included: case reports, series, or cohorts with (i) EYA1 SNVs/indels or CNVs and (ii) patient-level clinical data covering ≥2 domains (branchial, otologic, renal, craniofacial, musculoskeletal). Excluded: reviews, functional-only/animal studies, or overlapping cohorts (retaining the most complete report).

2.4. Screening and Data Extraction

Two reviewers independently screened titles/abstracts, followed by a full-text review. Extracted data included demographics, clinical features (categorized as BORSD-typical or OTFCS-typical), variant type (missense, truncating, splice, indel, stop-loss, structural/CNV), and deletion coordinates. All variants were described according to HGVS nomenclature using the EYA1 transcript NM_000503.6 and mapped to GRCh38. Duplicates were removed.

3. Clinical Presentation

A 22-year-old female, born at term, second child of healthy non-consanguineous parents, presented with severe congenital bilateral mixed hearing loss, bilateral preauricular fistulas, hypoplasia of the left shoulder muscles, winged scapula, short stature (<3rd percentile), and a history of speech delay. Chromosome analysis revealed a normal female karyotype (46,XX). Analysis of the EYA1 gene was negative for variants using sequencing approaches. MLPA analysis identified a heterozygous de novo deletion encompassing the entire coding region of EYA1 at 8q13.3. CMA (Figure 1) confirmed a 2.3 Mb interstitial deletion at 8q13.2q13.3 chromosomal region, which spanned from nucleotides 69,068,130 to 71,362,732 (GRCh38) and involved 12 genes (LINC01592, LINC01603, SULF1, SLCO5A1, PRDM14, NCOA2, LOC101926892, TRAM1, LACTB2-AS1, LACTB2, XKR9, EYA1), and which are further characterized in Table 2. The microdeletion occurred de novo because both parents were wild-type.

4. Results

The search retrieved more than 200 records in PubMed and additional records in Scopus, Embase and Google Scholar; after deduplication and eligibility screening, 55 studies and 141 reported SNVs were included, as described in Supplementary Materials. Among these, 54 (38.3%) were frameshift variants (fs), 30 (21.3%) were nonsense variants (ns), 28 (19.9%) were splice-site variants (sp), 26 (18.4%) were missense variants (ms), 2 (1.4%) were stop-loss/stop-like variants (sl), and 1 (0.7%) was annotated as an indel (Figure 2). EYA1 gene SNVs found in the literature in association with OTFCS/BORSD spectrum are shown in Table 3, according to the first accession of genotype and/or complete phenotype. 1 splice site variant was associated with a single OTFCS case, 1 missense variant was associated with unrelated OTFCS and BORSD cases, while all the remainder SNVs were detected within the BORSD spectrum. Renal involvement is apparently absent in association with 34/141 (24.1%) described SNVs, regardless of the type of variant (ns, fs, sp, ms, sl) within the BORSD spectrum. OTFCS cases (both due to SNVs and CNVs) are further characterized in Table 4 and compared to the reported case.
In addition to the distribution of variant classes, our analysis revealed that large EYA1 deletions are enriched among BORSD cases, accounting for approximately 20% of the reports in the literature. Moreover, two-thirds of reported EYA1 SNVs were predicted to be LoF, consistent with haploinsufficiency as the main disease mechanism.

5. Discussion

The present review highlights the complex relationship between BORSD and OTFCS, both associated with EYA1 copy number and sequence variants. BORSD has traditionally been defined by a triad of branchial, otologic, and renal anomalies [7,18]. In contrast, OTFCS has been described as a distinct condition, characterized by musculoskeletal anomalies such as scapular dysplasia and short stature [9,14]. However, our systematic analysis and the present case emphasize that considerable phenotypic overlap exists, and that classical BORSD features may co-occur with OTFCS hallmarks.
The EYA proteins are components of a conserved regulatory network that is often referred to as the PAX–SIX–EYA–DACH developmental network (PSEDN) to better reflect the proteins involved [69]. This network plays a key regulatory role in the early development of multiple organs [70,71]. Notably, all known disease genes implicated in BORSD and OTFCS belong to this network. While OTFCS has also been genetically linked to PAX1 [4,14] and, in a limited number of patients, EYA4 in [19], EYA1 remains the major gene implicated in conditions.
Pathogenic EYA1 variants encompass truncating, missense, splice-site, stop-loss, and copy-number alterations, and have been documented in association with BORSD, OTFCS, and intermediate phenotypes [6,62]. Within our case series, one SNV in the EYA1 gene was described exclusively in association with OTFCS (1/141; 0.7%), one SNV was described in association with both OTFCS and BORSD (1/141; 0.7%), while the remainder (139/141; 98.6%) were described within the BORSD spectrum, with or without renal involvement. Thus, the variant class alone may be insufficient to predict the clinical presentation. This supports the view that haploinsufficiency is the predominant disease mechanism [72,73], but additional genetic or environmental modifiers likely influence phenotypic expressivity. Importantly, the observation that OTFCS can also result from missense and splice variants, and not exclusively from large deletions, further challenges the concept of OTFCS as a purely contiguous gene deletion syndrome [9,14]. Complex rearrangements, inversions, and insertions further contribute to the mutational spectrum [74,75].
A particularly noteworthy finding from our review is that the majority of published patients with OTFCS due to EYA1 defects presented with renal anomalies, while in approximately 25% of EYA1-related cases of BORSD, they were absent regardless of the variant type. Since renal involvement has been traditionally associated with BORSD, this observation undermines the concept of a strict clinical separation between the two syndromes. Instead, it suggests that musculoskeletal involvement in OTFCS and renal anomalies in BORSD are not mutually exclusive, but somewhat variable manifestations of the same allelic defect. Conversely, OTFCS caused by other genetic mechanisms may represent distinct subtypes, supporting the concept of a subclassification of OTFCS according to the underlying molecular etiology.
To our knowledge, this is the first reported case of OTFCS due to an EYA1 defect characterized by Chromosomal Microarray (CMA). This provides a precise genomic definition of the 8q13.2q13.3 microdeletion underlying the phenotype and allows a detailed assessment of co-deleted genes. We also acknowledge that the interpretation of microdeletion cases is complicated by the involvement of multiple genes. In our case, the 8q13.2q13.3 deletion spans additional genes besides EYA1. We therefore reviewed their known or predicted functions. Although some have roles in developmental pathways, none have been consistently implicated in renal or musculoskeletal phenotypes resembling BORSD or OTFCS. Thus, while we cannot completely rule out modifying effects from neighboring genes, the current evidence supports EYA1 haploinsufficiency as the principal driver of both the craniofacial–musculoskeletal anomalies and the renal phenotype in our patient.
The wide spectrum of presentations of EYA1-related disorders suggests that modifying factors, such as genetic background, environmental influences, or stochastic events during development, may critically modulate the expressivity of EYA1 variants [76]. Analogous patterns are well recognized in other genetic conditions such as COL2A1 (Collagen, Type II, Alpha-1)-related skeletal dysplasias and TBX6 (T-Box Transcription Factor 6)-related segmentation defects, where allelic heterogeneity and modifiers account for wide phenotypic variability [77,78,79,80]. Rather than being distinct syndromes, BORSD and OTFCS may represent different clinical expressions of EYA1 dysfunction within the context of the broader PSEDN. Reports of identical or highly similar EYA1 anomalies resulting in divergent phenotypes in different families further support this model [35,72,81].
From a clinical standpoint, acknowledging OTFCS and BORSD as allelic disorders has significant implications. It underscores the need to systematically evaluate musculoskeletal and developmental features in patients diagnosed with BORSD, and conversely, to ensure comprehensive renal and auditory assessments in patients with OTFCS. Grouping both under the umbrella of EYA1-related disorders would enhance and streamline variant interpretation, strengthen genetic counseling, and support the development of follow-up protocols that integrate renal, otologic, and skeletal surveillance.
Future studies should pursue three main directions: (i) large-scale genotype–phenotype analyses integrating both BORSD and OTFCS cases; (ii) functional studies to elucidate the molecular impact of different EYA1 variants; and (iii) investigation of potential second-site modifiers within the PSEDN Network that might influence phenotypic outcome.

6. Conclusions

Our findings consolidate the model of BORSD and OTFCS as allelic disorders within a unified EYA1-related spectrum. This reclassification is critical for clinical practice: it improves diagnostic accuracy, mandates comprehensive phenotyping—most notably, systematic renal screening in all OTFCS patients—and refines prognostic and genetic counseling. Future research integrating deep phenotyping, genomic data, and functional studies will be essential to elucidate the mechanisms underlying the striking phenotypic variability within this spectrum.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/genes16111267/s1, Supplementary File: Flow diagram for literature review and data extraction via databases and registers.

Author Contributions

Conceptualization, L.G. and M.L.C.; Methodology, L.G.; Software, B.A.; Validation, O.P., S.M. and M.B.; Formal Analysis, O.P. and B.A.; Investigation, M.B.; Resources, G.N.; Data Curation, O.P.; Writing—Original Draft Preparation, L.G. and M.L.C.; Writing—Review & Editing, M.C. and G.N.; Visualization, M.L.C.; Supervision, M.C. and M.B.; Project Administration, G.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable. Ethical approval was waived for this study. No supplementary analysis was performed on the patients, except for the diagnostic genetic test.

Informed Consent Statement

The study was conducted according to the guidelines of the Declaration of Helsinki. We obtained written consent from the patients beforehand, as required by our regulations. The human samples used in this study were acquired from a by-product of routine care or industry.

Data Availability Statement

All datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Acknowledgments

The authors would like to thank the family for their generous participation in this study.

Conflicts of Interest

The authors declare no conflicts of interest.

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Genes 16 01267 g001
Figure 1. The molecular karyotype of the novel patient and the associated genes, adapted from the UCSC Genome Browser according to the International System for Human Cytogenetic Nomenclature (ISCN 2024): arr[GRCh38] 8q13.2q13.3(69,068,130_71,362,732)×1.
Figure 1. The molecular karyotype of the novel patient and the associated genes, adapted from the UCSC Genome Browser according to the International System for Human Cytogenetic Nomenclature (ISCN 2024): arr[GRCh38] 8q13.2q13.3(69,068,130_71,362,732)×1.
Genes 16 01267 g001
Genes 16 01267 g002
Figure 2. Graphical representation of variants in the EYA1 (NM_000503.6) gene reported in medical and scientific literature (PubMed, Scopus, Google Scholar) in association with BORSD/OTFCS phenotypes. In yellow, frameshift variants; in purple, splicing variants; in red, nonsense variants; in blue, missense variants; in black, stop-loss variants; in grey, in/del variants. Variant visualization was generated using ProteinPaint Release version: 2.147.0-ecd631c6f (St. Jude Children’s Research Hospital, Memphis, TN, USA; https://proteinpaint.stjude.org (accessed on 25 September 2025).
Figure 2. Graphical representation of variants in the EYA1 (NM_000503.6) gene reported in medical and scientific literature (PubMed, Scopus, Google Scholar) in association with BORSD/OTFCS phenotypes. In yellow, frameshift variants; in purple, splicing variants; in red, nonsense variants; in blue, missense variants; in black, stop-loss variants; in grey, in/del variants. Variant visualization was generated using ProteinPaint Release version: 2.147.0-ecd631c6f (St. Jude Children’s Research Hospital, Memphis, TN, USA; https://proteinpaint.stjude.org (accessed on 25 September 2025).
Genes 16 01267 g002
Table 1. Genotypic and phenotypic overlapping within the branchiootorenal and Otofaciocervical syndrome spectrum.
Table 1. Genotypic and phenotypic overlapping within the branchiootorenal and Otofaciocervical syndrome spectrum.
Disorder Genotype Phenotype
GeneOMIMInher.BranchialEarRenalEyeMusculoskeletalNeurologicImmunologic
BORS
Type 1EYA1113650AD+++±−−−
Type 2SIX5610896AD+++−−−−
BOS
Type 1EYA1120502AD++−±−−−
Type 2-602588AD++−−−−−
Type 3SIX1608389AD++−−−−−
OTFCS
Type 1EYA1166780AD+++−++±
Type 2PAX1615560AR++−±+++
BORS, Branchiootorenal syndrome; BOS, Branchiootic syndrome; OTFCS, Otofaciocervical syndrome; AD, Autosomal dominant; AR, Autosomal recessive; OMIM, Online Mendelian Inheritance in Man; +, present; −, absent; ± variable.
Table 2. OMIM genes within the patient’s deleted chromosomal region. pHaplo dosage sensitivity index is presented, where high ranks (i.e., 0.8–1.0) indicate a gene is more likely to exhibit haploinsufficiency and low ranks (i.e., 0.0–0.20) indicate a gene is more likely not to exhibit haploinsufficiency.
Table 2. OMIM genes within the patient’s deleted chromosomal region. pHaplo dosage sensitivity index is presented, where high ranks (i.e., 0.8–1.0) indicate a gene is more likely to exhibit haploinsufficiency and low ranks (i.e., 0.0–0.20) indicate a gene is more likely not to exhibit haploinsufficiency.
GeneMIM NumberpHaploPhenotypesNotes
EYA16016530.90BORS, OTFCS.-
LACTB26189210.31-May have a role in mitochondrial function and cell viability (Yu et al., 2016) [25]
NCOA26019930.99-Encodes a nuclear receptor coactivator, which aids in the function of nuclear hormone receptors (Cai et al., 2019) [26]
PRDM146117810.59-Gene amplification has frequently been observed in human tumors (Nishikawa et al., 2007) [27]
SLCO5A16135430.35-Highly expressed in fetal and adult brain and heart (Isidor et al., 2010) [28]
SULF16100120.66-Involved in cell signaling by heparin-binding growth factors (Lai et al., 2003) [29]
TRAM16051900.88-Functional analysis indicated that it influences glycosylation and is stimulatory or required for the translocation of secretory proteins (Gorlich et al., 1992) [30]
BORS, Branchiootorenal syndrome; AD, Autosomal dominant; OTFCS, Otofaciocervical syndrome; OMIM, Online Mendelian Inheritance in Man.
Table 3. EYA1 variants have been reported in patients with branchiootorenal spectrum disorders (BORSD), branchiootic (BO) syndrome, or otofaciocervical syndrome (OTFCS). Variants are described according to the HGVS nomenclature, using the reference transcript NM_000503.6 (EYA1) and mapped to the human genome assembly GRCh38. Variant types are classified as missense (ms), nonsense (ns), frameshift (fs), splice (sp), insertion/deletion (indel), or stoploss (sl). Clinical diagnoses are reported as indicated in the original publications, grouped into BOR, BO, OTFCS, or overlapping phenotypes. Only molecularly confirmed cases with sufficient clinical description were included. References correspond to the first report of each genotype–phenotype association.
Table 3. EYA1 variants have been reported in patients with branchiootorenal spectrum disorders (BORSD), branchiootic (BO) syndrome, or otofaciocervical syndrome (OTFCS). Variants are described according to the HGVS nomenclature, using the reference transcript NM_000503.6 (EYA1) and mapped to the human genome assembly GRCh38. Variant types are classified as missense (ms), nonsense (ns), frameshift (fs), splice (sp), insertion/deletion (indel), or stoploss (sl). Clinical diagnoses are reported as indicated in the original publications, grouped into BOR, BO, OTFCS, or overlapping phenotypes. Only molecularly confirmed cases with sufficient clinical description were included. References correspond to the first report of each genotype–phenotype association.
Genotype PhenotypeReference
CDS (c.)Protein (p.)Exon(s)Variant type Author
164C>TThr55Met4msBOROrten et al., Hum. Mutat. (2008) [31]
283C>TPro62Ser6msBORKrug et al., Hum. Mutat. (2011) [11]
321delAla108HisfsTer1336fsBORLee et al., Ann. Clin. Lab Sci. (2009) [32]
348delGly117GlufsTer1246fsBOROrten et al., Hum. Mutat. (2008) [31]
402C>AGly107Ser6msBOROrten et al., Hum. Mutat. (2008) [31]
418G>AGly140Ser6msBOR/BOKrug et al., Hum. Mutat. (2011), Kim et al., Mol. Biol. Rep. (2014) [11,33]
418+1G>CInvariant ‘gt’IVS6spBORUnzaki et al., J. Hum. Genet. (2018) [24]
450_451delGly151IlefsTer367fsBOROrten et al., Hum. Mutat. (2008) [31]
466C>TGln156Ter7nsBORWang et al., Laryngoscope (2012) [34]
525delGly176AspfsTer657fsBORKlingbeil et al., Int. J. Pediatr. Otorhinolaryngol. (2017) [35]
529C>TGln177Ter7nsBORKrug et al., Hum. Mutat. (2011) [11]
553C>TGln185Ter7nsBOROrten et al., Hum. Mutat. (2008) [31]
588T>GTyr196Ter8nsBOIdeura et al., Sci. Rep. (2019) [36]
592G>TGly198Ter8nsBOROrten et al., Hum. Mutat. (2008) [31]
602C>GSer201Ter8nsBOOrten et al., Hum. Mutat. (2008) [31]
634C>TGln212Ter8nsBOROrten et al., Hum. Mutat. (2008) [31]
638A>TGln213Leu8msBOROrten et al., Hum. Mutat. (2008) [31]
639G>CGln213His8msBOROrten et al., Hum. Mutat. (2008) [31]
639+1G>AInvariant ‘gt’IVS8spOTFCEstefanía et al., Ann. Hum. Genet. (2006) [13]
639+1G>CInvariant ‘gt’IVS8spBOROrten et al., Hum. Mutat. (2008) [31]
639+2delInvariant ‘gt’IVS8spBOROrten et al., Hum. Mutat. (2008) [31]
639+3A>Cexon skippingIVS8spBORZhang et al., BMC Med. Genomics (2024) [37]
640-15G>ANew splice acceptorIVS8spBOROrten et al., Hum. Mutat. (2008) [31]
769delGln257SerfsTer1099fsBORKrug et al., Hum. Mutat. (2011) [11]
678C>ATyr226Ter9nsBORRiedhammer et al., Eur. J. Hum. Genet. (2023) [38]
685_695dupSer233IlefsTer129fsBORKrug et al., Hum. Mutat. (2011) [11]
698C>ASer233Ter9nsBORUnzaki et al., J. Hum. Genet. (2018) [24]
715dupTyr239LeufsTer509fsBORKrug et al., Hum. Mutat. (2011) [11]
735_743delCAGCCCAACinsTGSer246GlyfsTer1189fsBORKrug et al., Hum. Mutat. (2011) [11]
768C>ATyr256Ter9nsBOOrten et al., Hum. Mutat. (2008) [31]
777dupGlu260ArgfsTer299fsBOROrten et al., Hum. Mutat. (2008) [31]
802C>TGln268Ter9nsBORCho et al., Int. J. Mol. Sci. (2024) [8]
821delThr274LysfsTer929fsBORKrug et al., Hum. Mutat. (2011) [11]
827-1G>CInvariant ‘at’IVS9spBORTang et al., Medicine (Baltimore) (2022) [39]
845_852delSer282AsnfsTer410fsBOROrten et al., Hum. Mutat. (2008) [31]
851C>GSer284Ter10nsBOROrten et al., Hum. Mutat. (2008) [31]
863_866delLys288IlefsTer7710fsBOROrten et al., Hum. Mutat. (2008) [31]
866delAsp289ValfsTer7710fsBOROrten et al., Hum. Mutat. (2008) [31]
875dupAsp293Ter10nsBOROrten et al., Hum. Mutat. (2008) [31]
880C>TArg294Ter10nsBORKumar et al., Genet. Test. (1997) [40]
882delLeu295CysfsTer7110fsBORKrug et al., Hum. Mutat. (2011) [11]
889C>TArg297Ter10fsBOR/BORickard et al., J. Med. Gen. (2000); Wang et al., Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi (2020) [41,42]
920delArg307fsTer36510fsBORSanggaard et al., Eur. J. Hum. Genet. (2007) [43]
922C>TArg308Ter10nsBOR/BOAbdelhak et al., Nat. Gen. (1997); Orten et al., Hum. Mutat. (2008) [31,44]
965A>GGlu322Gly10msBOR/BOSong et al., PloS ONE (2013) [45]
966+5G>A?IVS10spBOR/BOKrug et al., Hum. Mutat. (2011); Stockley et al., Am. J. Med. Genet. A (2009) [11,23]
966_966+14delsplice junction lossIVS10fsBORKrug et al., Hum. Mutat. (2011) [11]
967-1G>AInvariant ‘ag’IVS10spBOROrten et al., Hum. Mutat. (2008) [31]
967-2A>GInvariant ‘ag’IVS10spBORKwon et al., Acta Otolaryngol. (2009) [46]
967A>TArg32311nsBORWang et al., BMC Med. Genet. (2018) [12]
977T>AIle326Asn11msBOROrten et al., Hum. Mutat. (2008) [31]
979T>CTrp327Arg11msBOKlingbeil et al., Int. J. Pediatr. Otorhinolaryngol. (2017) [35]
979T>GTrp327Gly11msBORMasuda et al., Sci. Rep. (2022) [47]
989A>TGlu330Val11msBORKrug et al., Hum. Mutat. (2011) [11]
1029delTyr344ThrfsTer2211fsBOROrten et al., Hum. Mutat. (2008) [31]
1050+1G>TInvariant ‘gt’IVS11spBOROrten et al., Hum. Mutat. (2008) [31]
1050+2T>CInvariant ‘gt’IVS11spBORUnzaki et al., J. Hum. Genet. (2018) [24]
1050+3G>T?IVS11spBORMasuda et al., Sci. Rep. (2022) [47]
1050+4A>Cexon skippingIVS11spBOChen et al., Clin. Exp. Otorhinolaryngol. (2023) [48]
1051-12T>GNew splice acceptorIVS11spBOOrten et al., Hum. Mutat. (2008) [31]
1051-1G>CInvariant ‘ag’IVS11spBOROkada et al., Pediatr. Nephrol. (2006) [49]
1054_1055insGPro352ArgfsTer2612fsBORMasuda et al., Sci. Rep. (2022) [47]
1075_1077delinsATGly359IlefsTer12fsBOXing et al., Int. J. Pediatr. Otorhinolaryngol. (2020) [50]
1081C>TArg361Ter12nsBOR/BOKumar et al., Genet. Test. (1997); Spruijt et al., Am. J. Med. Gen. A (2006) [40,51]
1088A>TGlu363Val12msBORKrug et al., Hum. Mutat. (2011) [11]
1138G>TGlu380Ter12nsBORKrug et al., Hum. Mutat. (2011) [11]
1140+1G>A?IVS12spBOR/BOSong et al., PloS ONE (2013) [45]
1171delSer391fsTer912fsBORLin et al., BMC Nephrol. (2023) [52]
1161_1164delIle387MetfsTer1212fsBOUnzaki et al., J. Hum. Genet. (2018) [24]
1118delHis373LeufsTer412fsBOOrten et al., Hum. Mutat. (2008) [31]
1122delLeu374PhefsTer612fsBORUnzaki et al., J. Hum. Genet. (2018) [24]
1138_1140+1delInvariant ‘gt’12; IVS12spBOROrten et al., Hum. Mutat. (2008) [31]
1140+1G>AInvariant ‘gt’IVS12spBOR/BOSong et al., PloS ONE (2013) [45]
1141-1G>AInvariant ‘ag’13fsBORSanggaard et al., Eur. J. Hum. Genet. (2007) [43]
1156delHis386IlefsTer213fsBOOrten et al., Hum. Mutat. (2008) [31]
1189C>TGln397Ter13nsBOIdeura et al., Sci. Rep. (2019) [36]
1199+1G>CInvariant ‘gt’IVS13spBORKrug et al., Hum. Mutat. (2011) [11]
1200-1G>AInvariant ‘ag’IVS13spBORetterer et al., Genet. Med. (2016) [53]
1220G>AArg407Gln14msBOCho et al., Int. J. Mol. Sci. (2024) [8]
1254_1255delCys419PhefsTer3214fsBOIdeura et al., Sci. Rep. (2019) [36]
1255delCys419ValfsTer1314fsBOMa et al., Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi (2021) [54]
1268delGly423ValfsTer914fsBOOrten et al., Hum. Mutat. (2008) [31]
1276G>AGly426Ser14msBORCho et al., Int. J. Mol. Sci. (2024) [8]
1286A>GAsp429Gly14msBONamba et al., J. Hum. Genet. (2001); Yalcouyé et al., Mol. Genet. Genomic Med. (2022) [55,56]
1289G>ATrp430Ter14nsBORUnzaki et al., J. Hum. Genet. (2018) [24]
1315_1318dupArg440GlnfsTer1314fsBORKrug et al., Hum. Mutat. (2011) [11]
1319G>AArg440Gln14msBORUnzaki et al., J. Hum. Genet. (2018) [24]
1329_1330Glu443AspfsTer814fsBORBałdyga et al., Genes (2023) [57]
1330_1331dupTyr445SerfsTer2414fsBORKrug et al., Hum. Mutat. (2011) [11]
1350delinsCCAsn451GlnfsTer1014fsBOAbdelhak et al., Nat. Genet. (1997) [44]
1360+4A>G?IVS14spBORSanggaard et al., Eur. J. Hum. Genet. (2007) [43]
1361-1G>AInvariant ‘ag’IVS14spBORRiedhammer et al., Eur. J. Hum. Genet. (2023) [38]
1377_1378 delinsATLys460Ter15nsBOROrten et al., Hum. Mutat. (2008) [31]
1381delArg461GlyfsTer715fsBORLi et al., Intractable Rare Dis. Res. (2018) [58]
1405delAla469ProfsTer615fsBOOrten et al., Hum. Mutat. (2008) [31]
1420_1421delLeu474AspfsTer5715fsBORNardi et al., Clin. Nephrol. (2011) [59]
1471_1474dupArg492LeufsTer4115fsBORKrug et al., Hum. Mutat. (2011) [11]
1475G>CArg492Pro15msBOROrten et al., Hum. Mutat. (2008) [31]
1475+1G>CInvariant ‘gt’15spBORGigante et al. BMC Nephrol.(2013) [60]
1476-2A>GInvariant ‘ag’IVS15spBOROrten et al., Hum. Mutat. (2008) [31]
1487delVal496GlyfsTer416fsBORMasuda et al., Sci. Rep. (2022) [47]
1493_1494insATIle498PhefsTer316fsBORChen et al., Int. J. Pediatr. Otorhinolaryngol. (2019) [61]
1496delLeu499Ter16nsBOROrten et al., Hum. Mutat. (2008) [31]
1510C>TGln504Ter16nsBOROrten et al., Hum. Mutat. (2008) [31]
1524delLeu509TrpfsTer916fsBORKrug et al., Hum. Mutat. (2011) [11]
1533dupVal512SerfsTer2016fsBORKrug et al., Hum. Mutat. (2011) [11]
1534G>TVal512Phe16msBOOrten et al., Hum. Mutat. (2008) [31]
1538T>CLeu513Pro16msBOOrten et al., Hum. Mutat. (2008) [31]
1541T>CLeu514Pro16msBO/OTFCKrug et al., Hum. Mutat. (2011); Mercer et al., Clin. Dysm. (2006) [11,15]
1570G>TGlu524Ter16nsBOOrten et al., Hum. Mutat. (2008) [31]
1579T>ATyr527Asn16msBOROrten et al., Hum. Mutat. (2008) [31]
1580A>Gyr527Cys16msBOROrten et al., Hum. Mutat. (2008) [31]
1591A>TLys531Ter16nsBOROrten et al., Hum. Mutat. (2008) [31]
1597G>AGly533Arg16msBOCastiglione et al., Int. J. Pediatr. Otorhinolaryngol. (2014) [6]
1597+1G>AInvariant ‘gt’IVS16spBORTian et al., Prenat. Diagn. (2024) [62]
1598-2A>CInvariant ‘at’IVS16spBOR/BOSong et al., PloS ONE (2013) [45]
1603_1607delGlu535LeufsTer317fsBOROrten et al., Hum. Mutat. (2008) [31]
1623_1626dupGln543AsnfsTer9017fsBORCho et al., Int. J. Mol. Sci. (2024) [8]
1627C>TGln543Ter17nsBORSpahiu et al., Balkan J. Med. Genet. (2016) [63]
1644delVal549TrpfsTer617fsBOOrten et al., Hum. Mutat. (2008) [31]
1641_1645delArg547SerfsTer8317fsBORKrug et al., Hum. Mutat. (2011) [11]
1643_1644dupVal549LysfsTer717fsBORUnzaki et al., J. Hum. Genet. (2018) [24]
1649T>AVal550Glu17msBOOrten et al., Hum. Mutat. (2008) [31]
1653T>GTyr551Ter17nsBORKrug et al., Hum. Mutat. (2011) [11]
1657_1659delVal553del17indelBOROrten et al., Hum. Mutat. (2008) [31]
1697dupHis567AlafsTer6517fsBOROrten et al., Hum. Mutat. (2008) [31]
1697_1698delAGinsTLys566IlefsTer7317fsBOHe et al., Front. Genet. (2024) [64]
1698+1G>TInvariant ‘gt’17spBOROrten et al., Hum. Mutat. (2008) [31]
1706T>CMet569Thr18msBOKrug et al., Hum. Mutat. (2011) [11]
1715G>TTrp572Leu18msBOFeng et al., Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi (2022) [65]
1715G>ATrp572Ter18nsBORCho et al., Int. J. Mol. Sci. (2024) [8]
1716G>ATrp572Ter18nsBOOrten et al., Hum. Mutat. (2008) [31]
1730_1745delHis577ProfsTer5718fsBOUnzaki et al., J. Hum. Genet. (2018) [24]
1735delAsp579ThrfsTer6018fsBORWang et al., Laryngoscope (2012) [34]
1744delAla582ProfsTer5718fsBOShao et al., Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi (2024) [66]
1754dupHis585GlnfsTer4718fsBORKrug et al., Hum. Mutat. (2011) [11]
1766dupGlu590GlyfsTer4218fsBORMasuda et al., Sci. Rep. (2022) [47]
1768delGlu590SerfsTer4918fsBOKlingbeil et al., Int. J. Pediatr. Otorhinolaryngol. (2017) [35]
1773C>GTyr591Ter18nsBOSanggaard et al., Eur. J. Hum. Genet. (2007) [43]
1777T>ATer593LysextTer618slBOKrug et al., Hum. Mutat. (2011) [11]
1777_1778delTAinsGTTer593Val18slBOMatsunaga et al., Acta Otolaryngol. (2007) [67]
?: unknown consequences.
Table 4. Reported patients with otofaciocervical syndrome (OTFCS) carrying EYA1 (NM_000503.6) variants, compared with the current case. Clinical features are grouped into core domains: HL = hearing loss; BA = branchial anomalies; EA = external ear anomalies; RA = renal anomalies; MSK = musculoskeletal anomalies; NDD = neurodevelopmental delay; ST = short stature. Additional findings are listed under “Other”. Variants are described according to NM_000503.6 (EYA1) and mapped to the GRCh38 assembly. Variant type was classified as single-nucleotide variant (SNV) or copy-number variant (CNV). Inheritance is indicated when available.
Table 4. Reported patients with otofaciocervical syndrome (OTFCS) carrying EYA1 (NM_000503.6) variants, compared with the current case. Clinical features are grouped into core domains: HL = hearing loss; BA = branchial anomalies; EA = external ear anomalies; RA = renal anomalies; MSK = musculoskeletal anomalies; NDD = neurodevelopmental delay; ST = short stature. Additional findings are listed under “Other”. Variants are described according to NM_000503.6 (EYA1) and mapped to the GRCh38 assembly. Variant type was classified as single-nucleotide variant (SNV) or copy-number variant (CNV). Inheritance is indicated when available.
ReferencePatients (n.)HLBAEARAMSKNDDSTOtherGenotype Variant TypeInheritance
Vincent et al., 1994 [68]1++NT+++−Hydrocephalus8q12.2–q21.2delCNVde novo
Rickard et al., 2001 [14]1+++++++−del(ex7,9,13)CNVde novo
2++++−+−−del(ex7,9,13)CNVde novo
Estefanía et al., 2006 [13]1+++++−−IgA deficiencyc.639+1G>ASNVde novo
Mercer et al., 2006 [15]1+++++++−c.1442T>CSNVNT
This study1+++−+++−8q13.2q13.3delCNVde novo
HL, hearing loss; BA, branchial anomalies; EA, ear anomalies; RA, renal anomalies; MSK, musculoskeletal anomalies; NDD, neurodevelopmental delay; ST, short stature; NT, not tested; CNV, copy number variant; SNV, single nucleotide variant. +, present; −, absent.
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Graziani, L.; Carriero, M.L.; Melchionda, S.; Augello, B.; Palumbo, O.; Bengala, M.; Castori, M.; Novelli, G. Otofaciocervical Syndrome and Its Overlap with Branchiootorenal Spectrum: An Integrated Literature Analysis of EYA1-Related Disorders, Including a Novel Case with an 8q13.2q13.3 Deletion. Genes 2025, 16, 1267. https://doi.org/10.3390/genes16111267

AMA Style

Graziani L, Carriero ML, Melchionda S, Augello B, Palumbo O, Bengala M, Castori M, Novelli G. Otofaciocervical Syndrome and Its Overlap with Branchiootorenal Spectrum: An Integrated Literature Analysis of EYA1-Related Disorders, Including a Novel Case with an 8q13.2q13.3 Deletion. Genes. 2025; 16(11):1267. https://doi.org/10.3390/genes16111267

Chicago/Turabian Style

Graziani, Ludovico, Miriam Lucia Carriero, Salvatore Melchionda, Bartolomeo Augello, Orazio Palumbo, Mario Bengala, Marco Castori, and Giuseppe Novelli. 2025. "Otofaciocervical Syndrome and Its Overlap with Branchiootorenal Spectrum: An Integrated Literature Analysis of EYA1-Related Disorders, Including a Novel Case with an 8q13.2q13.3 Deletion" Genes 16, no. 11: 1267. https://doi.org/10.3390/genes16111267

APA Style

Graziani, L., Carriero, M. L., Melchionda, S., Augello, B., Palumbo, O., Bengala, M., Castori, M., & Novelli, G. (2025). Otofaciocervical Syndrome and Its Overlap with Branchiootorenal Spectrum: An Integrated Literature Analysis of EYA1-Related Disorders, Including a Novel Case with an 8q13.2q13.3 Deletion. Genes, 16(11), 1267. https://doi.org/10.3390/genes16111267

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