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

A peer-reviewed version of this preprint was published in:
Genes 2025, 16(11), 1267. https://doi.org/10.3390/genes16111267

Submitted:

01 September 2025

Posted:

03 September 2025

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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 branchio-oto-renal spectrum disorders (BORSD)—both linked to EYA1 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 perform a review of 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.
Keywords: 
EYA1
;  
BORSD
;  
OTFCS
;  
genotype–phenotype correlations
;  
allelic disorders
;  
8q13.3
Subject: 
Medicine and Pharmacology  -   Other

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 branchio-oto-renal 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 (eye 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 mutations 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 variants in EYA4 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), and variant analysis was carried out with Coffalyser.Net software (MRC-Holland). 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. Results

3.1. Clinical and Molecular Data

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). The patient previously tested negative for sequence analysis of the EYA1 gene. MLPA analysis identified a heterozygous de novo deletion encompassing the entire coding region of EYA1 at 8q13.3. CMA analysis (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). The microdeletion occurred de novo because both parents resulted wild-type.

3.2. Literature Review and Data Extraction

The search retrieved more than 200 records in PubMed and additional records in Scopus; after deduplication and eligibility screening, 55 studies and 141 reported SNVs were included. 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 OTFC/BORSD spectrum are shown in Table 2, according to the first accession of genotype and/or complete phenotype. OTFCS cases are further characterized in Table 3.

4. 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 reflect better the proteins involved [25]. This network plays a key regulatory role in the early development of multiple organs [26,27]. Notably, all known disease genes implicated in BORSD and OTFCS belong to this network. While OTFCS has also been genetically linked to PAX1 and, in a limited number of patients, EYA4 in [4,14,19], 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 [6,28]. The variant class alone is insufficient to predict the clinical presentation. We observed that large EYA1 deletions are enriched among BORSD cases, accounting for about 20% of cases in the literature [29,30], and two-thirds of reported EYA1 SNVs were predicted to be loss-of-function (LoF), consistent with the notion that haploinsufficiency is the main disease mechanism. Conversely, OTFCS – which has been hypothesized as a contiguous gene deletion syndrome [14]– has also been observed with missense and splice variants [13,15]. Complex rearrangements, inversions, and insertions further contribute to the mutational spectrum [31,32].
A particularly noteworthy finding from our review is that all published patients with OTFCS due to EYA1 defects presented with renal anomalies. 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.
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 [33]. Analogous patterns are well recognized in other genetic conditions such as COL2A1-related skeletal dysplasias and TBX6-related segmentation defects, where allelic heterogeneity and modifiers account for wide phenotypic variability [34,35,36,37]. 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 [29,38,39].
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.

5. 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.

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.

Funding

No fundings.

Availability of data and materials

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, and acknowledge the use of ProteinPaint, developed by St. Jude Children’s Research Hospital, for variant visualization.

Conflict of interests

The authors declare no conflict of interest.

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Figure 1. The molecular karyotype of the novel patient, according with the International System for Human Cytogenetic Nomenclature (ISCN 2024), is: arr[GRCh38] 8q13.2q13.3(69,068,130_71,362,732)x1.
Figure 1. The molecular karyotype of the novel patient, according with the International System for Human Cytogenetic Nomenclature (ISCN 2024), is: arr[GRCh38] 8q13.2q13.3(69,068,130_71,362,732)x1.
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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/de variants. Variant visualization was generated using ProteinPaint (St. Jude Children’s Research Hospital, Memphis, TN; https://proteinpaint.stjude.org).
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/de variants. Variant visualization was generated using ProteinPaint (St. Jude Children’s Research Hospital, Memphis, TN; https://proteinpaint.stjude.org).
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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.
Disoder Genotype Phenotype
Gene OMIM Inher. Branchial Ear Renal Eye Musculoskeletal Neurologic Immunologic
BORS
Type 1 EYA1 113650 AD + + + ± - - -
Type 2 SIX5 610896 AD + + + - - - -
 
BOS
Type 1 EYA1 120502 AD + + - ± - - -
Type 2 - 602588 AD + + - - - - -
Type 3 SIX1 608389 AD + + - - - - -
 
OTFCS
Type 1 EYA1 166780 AD + + + - + + ±
Type 2 PAX1 615560 AR + + - ± + + +
BORS, Branchiootorenal syndrome; BOS, Branchiootic syndrome; OTFCS, Otofaciocervical syndrome; AD, Autosomal dominant; AR, Autosomal recessive.
Table 2. EYA1 variants have been reported in patients with branchio-oto-renal spectrum disorders (BORSD), branchio-otic (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 2. EYA1 variants have been reported in patients with branchio-oto-renal spectrum disorders (BORSD), branchio-otic (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 Phenotype Reference
CDS (c.) Protein (p.) Exon(s) Variant type Author
 
164C>T Thr55Met 4 ms BOR Orten et al., Hum. Mutat. (2008)[40]
283C>T Pro62Ser 6 ms BOR Krug et al., Hum. Mutat. (2011)[11]
321del Ala108HisfsTer133 6 fs BOR Lee et al., Ann. Clin. Lab Sci. (2009)[41]
348del Gly117Glufs*124 6 fs BOR Orten et al., Hum. Mutat. (2008)[40]
402C>A Gly107Ser 6 ms BOR Orten et al., Hum. Mutat. (2008)[40]
418G>A Gly140Ser 6 ms BOR/BO Krug et al., Hum. Mutat. (2011), Kim et al., Mol. Biol. Rep. (2014)[11,42]
418+1G>C Invariant ‘gt’ IVS6 sp BOR Unzaki et al., J. Hum. Genet. (2018)[24]
450_451del Gly151IlefsTer36 7 fs BOR Orten et al., Hum. Mutat. (2008)[40]
466C>T Gln156Ter 7 ns BOR Wang et al., Laryngoscope (2012)[43]
525del Gly176AspfsTer65 7 fs BOR Klingbeil et al., Int J Pediatr Otorhinolaryngol. (2017)
529C>T Gln177Ter 7 ns BOR Krug et al., Hum. Mutat (2011)[11]
553C>T Gln185Ter 7 ns BOR Orten et al., Hum. Mutat. (2008)[40]
588T>G Tyr196Ter 8 ns BO Ideura et al., Sci. Rep. (2019)[44]
592G>T Gly198Ter 8 ns BOR Orten et al., Hum. Mutat. (2008)[40]
602C>G Ser201Ter 8 ns BO Orten et al., Hum. Mutat. (2008)[40]
634C>T Gln212Ter 8 ns BOR Orten et al., Hum. Mutat. (2008)[40]
638A>T Gln213Leu 8 ms BOR Orten et al., Hum. Mutat. (2008)[40]
639G>C Gln213His 8 ms BOR Orten et al., Hum. Mutat. (2008)[40]
639+1G>A Invariant ‘gt’ IVS8 sp OTFC Estefanía et al., Ann. Hum. Genet. (2006)[13]
639+1G>C Invariant ‘gt’ IVS8 sp BOR Orten et al., Hum. Mutat. (2008)[40]
639+2del Invariant ‘gt’ IVS8 sp BOR Orten et al., Hum. Mutat. (2008)[40]
639+3A>C exon skipping IVS8 sp BOR Zhang et al., BMC Med. Genomics (2024)[45]
640-15G>A New splice acceptor IVS8 sp BOR Orten et al., Hum. Mutat. (2008)[40]
769del Gln257SerfsTer109 9 fs BOR Krug et al., Hum. Mutat (2011)[11]
678C>A Tyr226Ter 9 ns BOR Riedhammer et al., Eur. J. Hum. Genet. (2023)[46]
685_695dup Ser233IlefsTer12 9 fs BOR Krug et al., Hum. Mutat (2011)[11]
698C>A Ser233Ter 9 ns BOR Unzaki et al., J. Hum. Genet. (2018)[24]
715dup Tyr239LeufsTer50 9 fs BOR Krug et al., Hum. Mutat (2011)[11]
735_743delCAGCCCAACinsTG Ser246GlyfsTer118 9 fs BOR Krug et al., Hum. Mutat (2011)[11]
768C>A Tyr256Ter 9 ns BO Orten et al., Hum. Mutat. (2008)[40]
777dup Glu260ArgfsTer29 9 fs BOR Orten et al., Hum. Mutat. (2008)[40]
802C>T Gln268Ter 9 ns BOR Cho et al., Int. J. Mol. Sci. (2024)[8]
821del Thr274LysfsTer92 9 fs BOR Krug et al., Hum. Mutat (2011)[11]
827-1G>C Invariant ‘at’ IVS9 sp BOR Tang et al., Medicine (Baltimore) (2022)[47]
845_852del Ser282AsnfsTer4 10 fs BOR Orten et al., Hum. Mutat. (2008)[40]
851C>G Ser284Ter 10 ns BOR Orten et al., Hum. Mutat. (2008)[40]
863_866del Lys288IlefsTer77 10 fs BOR Orten et al., Hum. Mutat. (2008)[40]
866del Asp289ValfsTer77 10 fs BOR Orten et al., Hum. Mutat. (2008)[40]
875dup Asp293Ter 10 ns BOR Orten et al., Hum. Mutat. (2008)[40]
880C>T Arg294Ter 10 ns BOR Kumar et al., Genet. Test. (1997)[48]
882del Leu295CysfsTer71 10 fs BOR Krug et al., Hum. Mutat (2011)[11]
889C>T Arg297Ter 10 fs BOR/BO Rickard et al., J. Med. Gen. (2000); Wang et al., Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi (2020)[49,50]
920del Arg307fsTer365 10 fs BOR Sanggaard et al., Eur. J. Hum. Genet. (2007)[51]
922C>T Arg308Ter 10 ns BOR/BO Abdelhak et al., Nat. Gen. (1997); Orten et al., Hum. Mutat. (2008)[40,52]
965A>G Glu322Gly 10 ms BOR/BO Song et al., PloS ONE (2013)[53]
966+5G>A ? IVS10 sp BOR/BO Krug et al., Hum. Mutat (2011); Stockley et al., Am. J. Med. Genet. A (2009)[11,23]
966_966+14del splice junction loss IVS10 fs BOR Krug et al., Hum. Mutat (2011)[11]
967-1G>A Invariant ‘ag’ IVS10 sp BOR Orten et al., Hum. Mutat. (2008)[40]
967-2A>G Invariant ‘ag’ IVS10 sp BOR Kwon et al., Acta Otolaryngol. (2009)[54]
967A>T Arg323 11 ns BOR Wang et al., BMC Med Genet (2018)[12]
977T>A Ile326Asn 11 ms BOR Orten et al., Hum. Mutat. (2008)[40]
979T>C Trp327Arg 11 ms BO Klingbeil et al., Int J Pediatr Otorhinolaryngol. (2017)[38]
979T>G Trp327Gly 11 ms BOR Masuda et al., Sci Rep (2022)[55]
989A>T Glu330Val 11 ms BOR Krug et al., Hum. Mutat (2011)[11]
1029del Tyr344ThrfsTer22 11 fs BOR Orten et al., Hum. Mutat. (2008)[40]
1050+1G>T Invariant ‘gt’ IVS11 sp BOR Orten et al., Hum. Mutat. (2008)[40]
1050+2T>C Invariant ‘gt’ IVS11 sp BOR Unzaki et al., J. Hum. Genet. (2018)[24]
1050+3G>T ? IVS11 sp BOR Masuda et al., Sci. Rep. (2022)[55]
1050+4A>C exon skipping IVS11 sp BO Chen et al., Clin. Exp. Otorhinolaryngol. (2023)[56]
1051-12T>G New splice acceptor IVS11 sp BO Orten et al., Hum. Mutat. (2008)[40]
1051-1G>C Invariant ‘ag’ IVS11 sp BOR Okada et al., Pediatr. Nephrol. (2006)[57]
1054_1055insG Pro352ArgfsTer26 12 fs BOR Masuda et al., Sci Rep (2022)[55]
1075_1077delinsAT Gly359IlefsTer 12 fs BO Xing et al., Int J Pediatr Otorhinolaryngol (2020)[58]
1081C>T Arg361Ter 12 ns BOR/BO Kumar et al., Genet. Test. (1997); Spruijt et al., Am. J. Med. Gen. A (2006)[48,59]
1088A>T Glu363Val 12 ms BOR Krug et al., Hum. Mutat (2011)[11]
1138G>T Glu380Ter 12 ns BOR Krug et al., Hum. Mutat (2011)[11]
1140+1G>A ? IVS12 sp BOR/BO Song et al., PloS ONE (2013)[53]
1171del Ser391fsTer9 12 fs BOR Lin et al., BMC Nephrol. (2023)[60]
1161_1164del Ile387MetfsTer12 12 fs BO Unzaki et al., J Hum Genet (2018)[24]
1118del His373LeufsTer4 12 fs BO Orten et al., Hum. Mutat. (2008)[40]
1122del Leu374PhefsTer6 12 fs BOR Unzaki et al., J Hum Genet (2018)[24]
1138_1140+1del Invariant ‘gt’ 12; IVS12 sp BOR Orten et al., Hum. Mutat. (2008)[40]
1140+1G>A Invariant ‘gt’ IVS12 sp BOR/BO Song et al., PloS ONE (2013)[53]
1141-1G>A Invariant ‘ag’ 13 fs BOR Sanggaard et al., Eur. J. Hum. Genet. (2007)[51]
1156del His386IlefsTer2 13 fs BO Orten et al., Hum. Mutat. (2008)[40]
1189C>T Gln397Ter 13 ns BO Ideura et al., Sci. Rep. (2019)[44]
1199+1G>C Invariant ‘gt’ IVS13 sp BOR Krug et al., Hum. Mutat (2011)[11]
1200-1G>A Invariant ‘ag’ IVS13 sp BO Retterer et al., Genet. Med. (2016)[61]
1220G>A Arg407Gln 14 ms BO Cho et al., Int. J. Mol. Sci. (2024)[8]
1254_1255del Cys419PhefsTer32 14 fs BO Ideura et al., Sci. Rep. (2019)[44]
1255del Cys419ValfsTer13 14 fs BO Ma et al., Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi (2021)[62]
1268del Gly423ValfsTer9 14 fs BO Orten et al., Hum. Mutat. (2008)[40]
1276G>A Gly426Ser 14 ms BOR Cho et al., Int. J. Mol. Sci. (2024)[8]
1286A>G Asp429Gly 14 ms BO Namba et al., J. Hum. Genet. (2001); Yalcouyé et al., Mol Genet Genomic Med (2022)[63,64]
1289G>A Trp430Ter 14 ns BOR Unzaki et al., J. Hum. Genet. (2018)[24]
1315_1318dup Arg440GlnfsTer13 14 fs BOR Krug et al., Hum. Mutat (2011)[11]
1319G>A Arg440Gln 14 ms BOR Unzaki et al., J. Hum. Genet. (2018)[24]
1329_1330 Glu443AspfsTer8 14 fs BOR Bałdyga et al., Genes (2023)[65]
1330_1331dup Tyr445SerfsTer24 14 fs BOR Krug et al., Hum. Mutat (2011)[11]
1350delinsCC Asn451GlnfsTer10 14 fs BO Abdelhak et al., Nat. Genet. (1997)[52]
1360+4A>G ? IVS14 sp BOR Sanggaard et al., Eur. J. Hum. Genet. (2007)[51]
1361-1G>A Invariant ‘ag’ IVS14 sp BOR Riedhammer et al., Eur. J. Hum. Genet. (2023)[46]
1377_1378 delinsAT Lys460Ter 15 ns BOR Orten et al., Hum. Mutat. (2008)[40]
1381del Arg461GlyfsTer7 15 fs BOR Li et al., Intractable Rare Dis Res (2018)[66]
1405del Ala469ProfsTer6 15 fs BO Orten et al., Hum. Mutat. (2008)[40]
1420_1421del Leu474AspfsTer57 15 fs BOR Nardi et al., Clin. Nephrol. (2011)[67]
1471_1474dup Arg492LeufsTer41 15 fs BOR Krug et al., Hum. Mutat (2011)[11]
1475G>C Arg492Pro 15 ms BOR Orten et al., Hum. Mutat. (2008)[40]
1475+1G>C Invariant ‘gt’ 15 sp BOR Gigante et al. BMC Nephrol.(2013)[68]
1476-2A>G Invariant ‘ag’ IVS15 sp BOR Orten et al., Hum. Mutat. (2008)[40]
1487del Val496GlyfsTer4 16 fs BOR Masuda et al., Sci Rep (2022)[55]
1493_1494insAT Ile498PhefsTer3 16 fs BOR Chen et al., Int J Pediatr Otorhinolaryngol. (2019)[69]
1496del Leu499Ter 16 ns BOR Orten et al., Hum. Mutat. (2008)[40]
1510C>T Gln504Ter 16 ns BOR Orten et al., Hum. Mutat. (2008)[40]
1524del Leu509TrpfsTer9 16 fs BOR Krug et al., Hum. Mutat (2011)[11]
1533dup Val512SerfsTer20 16 fs BOR Krug et al., Hum. Mutat (2011)[11]
1534G>T Val512Phe 16 ms BO Orten et al., Hum. Mutat. (2008)[40]
1538T>C Leu513Pro 16 ms BO Orten et al., Hum. Mutat. (2008)[40]
1541T>C Leu514Pro 16 ms BO/OTFC Krug et al., Hum. Mutat (2011); Mercer et al., Clin. Dysm. (2006) [11,15]
1570G>T Glu524Ter 16 ns BO Orten et al., Hum. Mutat. (2008)[40]
1579T>A Tyr527Asn 16 ms BOR Orten et al., Hum. Mutat. (2008)[40]
1580A>G yr527Cys 16 ms BOR Orten et al., Hum. Mutat. (2008)[40]
1591A>T Lys531Ter 16 ns BOR Orten et al., Hum. Mutat. (2008)[40]
1597G>A Gly533Arg 16 ms BO Castiglione et al., Int J Pediatr Otorhinolaryngol. (2014)[6]
1597+1G>A Invariant ‘gt’ IVS16 sp BOR Tian et al., Prenat. Diagn. (2024)[28]
1598-2A>C Invariant ‘at’ IVS16 sp BOR/BO Song et al., PloS ONE (2013)[53]
1603_1607del Glu535LeufsTer3 17 fs BOR Orten et al., Hum. Mutat. (2008)[40]
1623_1626dup Gln543AsnfsTer90 17 fs BOR Cho et al., Int. J. Mol. Sci. (2024)[8]
1627C>T Gln543Ter 17 ns BOR Spahiu et al., Balkan J Med Genet. (2016)[70]
1644del Val549TrpfsTer6 17 fs BO Orten et al., Hum. Mutat. (2008)[40]
1641_1645del Arg547SerfsTer83 17 fs BOR Krug et al., Hum. Mutat (2011)[11]
1643_1644dup Val549LysfsTer7 17 fs BOR Unzaki et al., J Hum Genet (2018)[24]
1649T>A Val550Glu 17 ms BO Orten et al., Hum. Mutat. (2008)[40]
1653T>G Tyr551Ter 17 ns BOR Krug et al., Hum. Mutat (2011)[11]
1657_1659del Val553del 17 indel BOR Orten et al., Hum. Mutat. (2008)[40]
1697dup His567AlafsTer65 17 fs BOR Orten et al., Hum. Mutat. (2008)[40]
1697_1698delAGinsT Lys566IlefsTer73 17 fs BO He et al., Front. Genet. (2024)[71]
1698+1G>T Invariant ‘gt’ 17 sp BOR Orten et al., Hum. Mutat. (2008)[40]
1706T>C Met569Thr 18 ms BO Krug et al., Hum. Mutat (2011)[11]
1715G>T Trp572Leu 18 ms BO Feng et al., Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi (2022)[72]
1715G>A Trp572Ter 18 ns BOR Cho et al., Int. J. Mol. Sci. (2024)[8]
1716G>A Trp572Ter 18 ns BO Orten et al., Hum. Mutat. (2008)[40]
1730_1745del His577ProfsTer57 18 fs BO Unzaki et al., J. Hum. Genet. (2018)[24]
1735del Asp579ThrfsTer60 18 fs BOR Wang et al., Laryngoscope (2012)[43]
1744del Ala582ProfsTer57 18 fs BO Shao et al., Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi (2024)[73]
1754dup His585GlnfsTer47 18 fs BOR Krug et al., Hum. Mutat (2011)[11]
1766dup Glu590GlyfsTer42 18 fs BOR Masuda et al., Sci Rep (2022)[55]
1768del Glu590SerfsTer49 18 fs BO Klingbeil et al., Int J Pediatr Otorhinolaryngol. (2017)[38]
1773C>G Tyr591Ter 18 ns BO Sanggaard et al., Eur. J. Hum. Genet. (2007)[51]
1777T>A Ter593LysextTer6 18 sl BO Krug et al., Hum. Mutat (2011)[11]
1777_1778delTAinsGT Ter593Val 18 sl BO Matsunaga et al., Acta Otolaryngol. (2007)[74]
Table 3. Reported patients with otofaciocervical syndrome (OTFCS) carrying EYA1 (NM_000503.6) variants. 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 3. Reported patients with otofaciocervical syndrome (OTFCS) carrying EYA1 (NM_000503.6) variants. 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.
Reference Patients (n.) HL BA EA RA MSK NDD ST Other Genotype Variant type Inheritance
Vincent et al., 1997 1 + + NT + + + - Hydrocefalus 8q12.2–q21.2del CNV de novo
Rickard et al., 2001 1 + + + + + + + - del(ex7,9,13) CNV de novo
2 + + + + - + - - del(ex7,9,13) CNV de novo
Estefanía et al., 2006 1 + + + + + - - IgA deficiency c.639+1G>A SNV de novo
Mercer et al., 2006 1 + + + + + + + - c.1442T>C SNV NT
This study 1 + + + + + + + - 8q13.2q13.3del CNV de novo
HL, hearing loss; BA, branchial anomalies; EA, ear anomalies; RA, renal anomalies; MSK, muskoloskeletal anomalies; NDD, neurodevelopmental delay; ST, short stature; NT, not tested; CNV, copy number variant; SNV, single nucleotide variant.
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