SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome

Abstract

Nager syndrome (NS) is a rare disease marked with craniofacial and preaxial limb anomalies. In this report, we summarized the current evidence to determine a possible genotype–phenotype association among NS individuals. Twenty-four articles comprising of 84 NS (including 9 patients with a severe form of NS [Rodriguez syndrome]) patients were examined, of which 76% were caused by variants in SF3B4 (OMIM *605593, Splicing Factor 3B, Subunit 4). Within the SF3B4 gene, variants located in exon 3 commonly occurred (20%) from a total identified variant, while hotspot location was identified in exon 1 (12%), and primarily occurred as frameshift variants (64%). Thirty-five distinct pathogenic variants within SF3B4 gene were identified with two common sites, c.1A > G and c.1060dupC in exons 1 and 5, respectively. Although no significant genotype–phenotype association was found, it is notable that patients with frameshift SF3B4 variants and predicted to lead to nonsense-mediated RNA decay (NMD) of the transcripts tended to have a more severe clinical manifestation. Additionally, patients harboring variants in exons 2 and 3 displayed a higher proportion of cardiac malformations. Taken together, this article summarizes the pathogenic variants observed in SF3B4 and provides a possible genotype–phenotype relationship in this disease.

Keywords

Nager syndrome rare disease craniofacial malformation genotype–phenotype correlation

Introduction

Nager syndrome (NS, preaxial acrofacial dysostosis or acrofacial dysostosis type 1 [AFD1]; MIM #154400) is a rare genetic disease that was first described in 1948 by Nager and de Reyenier, and is characterized by craniofacial anomalies and limb malformations.^1–3 To date, less than 100 NS cases have been reported.¹ The identification is often challenging due to overlapping phenotypes with other craniofacial anomalies such as Miller syndrome, mandibulofacial dysostosis with microcephaly (MFDM), and Treacher Collins syndrome (TCS). Recently, however, the lowered cost of sequencing has allowed physicians to identify the syndrome by genetic testing.

Although most cases are the result of de novo variants, evidence suggests that NS could be inherited both in autosomal dominant and recessive manner.^4–6 Bernier et al. first described that haploinsufficiency of SF3B4 is responsible for more than 50% of clinically diagnosed patients, which was also supported by the study of Petit et al. and Czeschik et al. in the following years.^3–5 However, it should be noted that no clear evidence of genotype–phenotype association has been reported in NS.² This is possibly due to the high variability of clinical expression among NS individuals and the limited reported cases. This report summarizes the current evidence and tries to seek for the possible genotype–phenotype correlations in NS.

Materials and Methods

Literature Search and Data Extraction

Dataset of the current analysis was identified by querying PubMed and Scopus with search terms such as “Nager syndrome”, “preaxial acrofacial dysostosis”, “SF3B4”, and “clinical features” up to June 12, 2021. Using this query, 122 and 41 records were retrieved from PubMed and Scopus, respectively (Figure 1). Records included in the study are (1) describing both completed molecular genetic testing and NS clinical features and (2) evaluating severe manifestation of NS (Rodriguez syndrome).⁷ Reference lists of retrieved articles were also manually screened to identify additional or potentially missing eligible studies. Data were retrieved from all selected publications and extracted as follows: (1) name of the first author; (2) year of publication; (3) country of origin; (4) age; (5) genetic information (including molecular genetic anomaly, cDNA position, exon location, and inheritance); and (6) 18 clinical features of NS (see Supplementary Table 1). In this study, all of the included SF3B4 variants were pathogenic or likely pathogenic (only study from Chummun et al. ⁸ was not determined due to lack of genetic information, Supplementary Table 1). All other variants of interests were not included in the analysis.

Figure 1.

Study flowchart for literature search and selection.

Statistical Analysis

The chi-square test was used to compare the proportions of qualitative variables between two groups (classical Fisher’s exact test was conducted if more than 20% of the expected frequencies are less than 5). If the number of the group exceeds 2, the chi-square test (alternatively, if more than 20% of the expected frequencies are less than 5 were observed, the Fisher-Freeman-Halton exact test was applied) followed by pairwise comparisons and Bonferroni correction was performed. All tests were two-sided with the significance level at .05. Statistical analysis was performed using the SPSS Version 25.

Results

Study Population and Hotspot Mutation in SF3B4

A total of 120 articles were screened, among which 24 passed the criteria and were further evaluated^1–24 (Figure 1). Details of the retrieved studies are shown in Supplementary Table 1. Eighty-four patients in those selected studies were further investigated, in which 64 of 84 patients (76%) were reported to have SF3B4 pathogenic variant, while the remaining 24% were caused by non-SF3B4 variants (Figure 2A). The current updated analysis found a higher percentage of SF3B4 variant than previously reported.^1,4,5 Variants in SF3B4 exon 3 are commonly occurred (20%) (Figure 2A). It should be noted that after the number of variants was adjusted by the number of nucleotides within each exon, the hotspot location was identified in exon 1 (12%, Supplementary Table 2). Among patients with SF3B4 variants, 86% (55 of 64 patients) consisted of NS, while only 14% (9 of 64 patients) were diagnosed with Rodriguez syndrome (Figure 2B). Moreover, we identified that 64% of SF3B4 pathogenic variants belonged to frameshift, followed by nonsense (19%) and variants resulting in loss of initiator methionine (17%) (Figure 2C). We summarized the identified distinct pathogenic SF3B4 variants in Figure 2D, with two common variants, c.1A > G (n = 8 patients) and c.1060dupC (n = 6 patients), located in exons 1 and 5, respectively.

Figure 2.

Genetics of Nager syndrome (NS). (A) Variant rate identified in known NS individuals. SF3B4 pathogenic variants contributed to 76% of the cases. Among them, 20% were located in exon 3, followed by 15% in exon 6. (B) Among patients with the SF3B4 variants, 86% were diagnosed with NS and 14% were classified as Rodriguez syndrome. (C) Three common types of variants were identified in patients with SF3B4 variants. Frameshift dominant the cases that contributed 65%, followed by nonsense variants (18%) and loss of initiator methionine (17%). (D) Schematic representation of SF3B4 gene with the variants summarized in this study, which with two common variants, c.1A > G (n = 8 patients) and c.1060dupC (n = 6 patients) were located in exons 1 and 5, respectively.

No Significant Association Between Clinical Features and Variants Within SF3B4 Exons

To identify an association between the clinical features and variants within SF3B4 exons, we compared the proportion of one clinical feature in patients with variants in exons 1 to 6. In general, we did not observe any significant association between the clinical features and the six exons studied (p-values for 17 of 18 clinical features were >.05), except patients with variants in exon 2 that exhibited a higher frequency of spinal and thoracic defects (3 of 4 patients, 75%, Table 1). Notably, we identified that congenital heart defect was observed more frequently in patients with variants located in exon 2 (2 of 4 patients, 50%) and 3 (5 of 17 patients, 29.4%).

Table 1.

Frequency of Clinical Features in Patients With and Without SF3B4 Variants.

Characteristics	SF3B4, Exon						p-value^a	SF3B4 (n = 64)	Non-SF3B4 (n = 20)	p-value^b
Characteristics	1 (n = 9)	2 (n = 4)	3 (n = 17)	4 (n = 8)	5 (n = 8)	6 (n = 13)	p-value^a	SF3B4 (n = 64)	Non-SF3B4 (n = 20)	p-value^b
Mandibular hypoplasia	88.9%	100%	100%	87.5%	100%	100%	.353	96.9%	85%	.085
Malar hypoplasia	66.7%	100%	82.4%	75%	62.5%	76.9%	.762	75%	75%	1.000
Down-slanting palpebral fissures	66.7%	50%	76.5%	87.5%	87.5%	84.6%	.632	76.6%	55%	.088
External ear anomalies	55.6%	100%	64.7%	75%	62.5%	92.3%	.289	71.9%	75%	1.000
Auditory canal stenosis	44.4%	100%	52.9%	50%	62.5%	69.2%	.477	57.8%	50%	.610
Hearing loss	33.3%	25%	50%	75%	25%	76.9%	.081	50%	30%	.132
Coloboma of lower eyelids	11.1%	25%	17.6%	12.5%	12.5%	30.8%	.858	17.2%	5%	.278
Dacryostenosis	11.1%	25%	0%	0%	12.5%	15.4%	.459	7.8%	5%	1.000
Abnormal palate	55.6%	50%	47.1%	50%	12.5%	61.5%	.411	45.3%	30%	.301
Facial asymmetry	0%	0%	11.8%	0%	12.5%	15.4%	.775	7.8%	10%	.669
TMJ anomaly	0%	25%	17.6%	12.5%	0%	15.4%	.633	10.9%	15%	.695
Psychomotor/speech delay	22.2%	25%	11.8%	0%	0%	30.8%	.294	14.1%	5%	.439
Upper limb anomalies	66.7%	100%	94.1%	100%	87.5%	100%	.096	90.6%	95%	1.000
Lower limb anomalies	22.2%	50%	47.1%	37.5%	37.5%	30.8%	.847	40.6%	20%	.114
Radioulnar synostosis	33.3%	25%	17.6%	62.5%	12.5%	30.8%	.259	28.1%	15%	.375
Congenital heart defect	0%	50%	29.4%	12.5%	12.5%	7.7%	.162	18.8%	30%	.351
Spine and thorax defects	0%	75%^a	11.8%^b	12.5%^ab	0%	7.7%^b	.005	10.9%	15%	.695
Genitourinary defects	11.1%	25%	11.8%	0%	0%	0%	.434	7.8%	20%	.207

The Fisher-Freeman-Halton exact test.

The classical Fisher’s exact test.

Bold text indicates a statistically significant difference with a p-value less than .05. Different letters indicate statistically significant differences (p < .05) [Bonferroni-corrected p-value (P_bonf) for exon 2 vs. exons 3 and 6 were 0.045 and 0.033, respectively; column with proportion is equal to zero or one was not used for comparisons].

Abbreviation: TMJ, temporomandibular joint.

No Significant Associations of Clinical Features Between SF3B4 Variants and Non-SF3B4 Variants

The clinical features in patients with or without SF3B4 variants were compared, and no significant associations (p-values for 18 of 18 clinical features were >.05) were found between the two groups. However, patients with SF3B4 variant tended to develop more severe phenotypes, characterized by a higher occurrence of mandibular hypoplasia and down-slanting palpebral fissures (Table 1). On a closer observation of two SF3B4 variant hotspots, c.1A > G and c.1060dupC, no major phenotypic differences between the two pathogenic variants were found (Table 2). Additionally, the three types of variants in SF3B4 were further compared, and patients with frameshift were likely to have relative severe features of NS such as auditory canal stenosis and upper limb anomalies (Table 2). Lastly, it should be noted that 9 out of 18 lethal cases (50%, Supplementary Table 1) were reported to have frameshift variants.

Table 2.

Frequency of Clinical Features in Patients With c.1A > G and c.1060dupC Pathogenic Variants and According to Variant Types.

Characteristics	SF3B4 hotspots			SF3B4 variant types
Characteristics	c.1A > G (n = 8)	c.1060dupC (n = 6)	p-value^a	Loss of initiator methionine (n = 9)	Frameshift (n = 38)	Nonsense (n = 12)	p-value^b
Mandibular hypoplasia	87.5%	100%	1.000	88.9%	97.4%	100%	.323
Malar hypoplasia	62.5%	66.7%	1.000	66.7%	78.9%	75%	.818
Down-slanting palpebral fissures	62.5%	100%	.209	66.7%	81.6%	75%	.662
External ear anomalies	62.5%	66.7%	1.000	55.6%	76.3%	75%	.478
Auditory canal stenosis	50%	66.7%	.627	44.4%^ab	76.3.%^a	16.7%^b	.0004
Hearing loss	37.5%	33.3%	1.000	33.3%	55.3%	58.3%	.444
Coloboma of lower eyelids	12.5%	16.7%	1.000	11.1%	21.1%	16.7%	.893
Dacryostenosis	0%	0%	1.000	11.1%	10.5%	0%	.641
Abnormal palate	50%	0%	.085	55.6%	44.7%	50%	.866
Facial asymmetry	0%	0%	1.000	0%	5.3%	25%	.074
TMJ anomaly	0%	0%	1.000	0%	10.5%	25%	.191
Psychomotor/speech delay	25%	0%	.473	22.2%	13.2%	16.7%	.869
Upper limb anomalies	62.5%	83.3%	.580	66.7%^b	97.4%^a	91.7%^a.b	.016
Lower limb anomalies	12.5%	50%	.245	22.2%	47.4%	16.7%	.103
Radioulnar synostosis	37.5%	16.7%	.580	33.3%	34.2%	8.3%	.273
Congenital heart defect	0%	16.7%	.429	0%	18.4%	25%	.315
Spine and thorax defects	0%	0%	1.000	0%	18.4%	0%	.144
Genitourinary defects	0%	0%	1.000	11.1%	7.9%	0%	.611

The classical Fisher’s exact test.

The Fisher-Freeman-Halton exact test.

Bold text indicates a statistically significant difference with a p-value less than .05. Different letters indicate statistically significant differences (p < .05) [Bonferroni-corrected p-value (P_bonf) for frameshift vs. nonsense = 0.001; Bonferroni-corrected p-value (P_bonf) for frameshift vs. loss of initiator methionine = 0.009].

Abbreviation: TMJ, temporomandibular joint.

SF3B4 Variants with NMD Resulted in Higher Occurrence of Spinal and Thoracic Defects

Since most of the SF3B4 variants are predicted to encode a truncated polypeptide chain or an elongated polypeptide with an altered 3′ end in the absence of nonsense-mediated RNA decay (NMD), we then identified the NMD potential targets among SF3B4 variants included in this study. When the proportion of phenotypic features in patients with and without NMD was compared, no significant associations were found between the two groups. However, patients with SF3B4 variants that are predicted to lead to NMD of the transcript could result in more severe phenotypes, such as a higher occurrence of upper limb anomalies (p < .05, Table 3).

Table 3.

Frequency of Clinical Features in Patients With and Without NMD Potential Targets among SF3B4 Pathogenic Variants.

Characteristics	SF3B4		p-value^a
Characteristics	NMD targets(n = 50)	Non-NMD targets(n = 9)	p-value^a
Mandibular hypoplasia	98%	88.9%	.284
Malar hypoplasia	78%	66.7%	.431
Down-slanting palpebral fissures	80%	66.7%	.398
External ear anomalies	76%	55.6%	.236
Auditory canal stenosis	62%	44.4%	.464
Hearing loss	56%	33.3%	.285
Coloboma of lower eyelids	20%	11.1%	1.000
Dacryostenosis	8%	11.1%	.577
Abnormal palate	46%	55.6%	.723
Facial asymmetry	10%	0%	1.000
TMJ anomaly	14%	0%	.581
Psychomotor/speech delay	14%	22.2%	.615
Upper limb anomalies	96%	66.7%	.022
Lower limb anomalies	40%	22.2%	.461
Radioulnar synostosis	28%	33.3%	.708
Congenital heart defect	20%	0%	.333
Spine and thorax defects	14%	0%	.581
Genitourinary defects	6%	11.1%	.494

The classical Fisher’s exact test.

Bold text indicates a statistically significant difference with a p-value less than .05.

Abbreviations: NMD, nonsense-mediated RNA decay; TMJ, temporomandibular joint.

Discussion

The pathogenesis of NS is still not fully understood. The formation of proper facial structure requires a highly regulated signaling mechanism, which involves both RNA biogenesis and the neural crest cells. The reported multifunctional roles of SF3B4 provide a hint for dissecting the disease mechanism. The SF3B4 encodes a spliceosome-associated protein, SAP49 that regulates RNA splicing by binding to the pre-mRNA and interacting with other U2 snRNPs.¹ The SAP49 has been shown to inhibit the BMP-mediated osteochondral cell, suggesting its involvement in skeletal development.⁵ Furthermore, suppression of neural crest genes (eg sox10, snail2, and twist) that lead to reduce the formation of craniofacial cartilages have been reported in Sf3b4-depleted Xenopus embryos.²⁵ Further fundamental biological studies could help us to unfold the pathogenesis of the disease.

Haploinsufficiency of SF3B4 is considered to be the major cause of NS, as a result of truncated or altered SF3B4 molecules.⁴ Our findings indicated that patients with frameshift variants in SF3B4 tended to have relatively severe NS manifestations, marked by higher proportions of auditory canal stenosis and upper limb anomalies, with 50% of cases being lethal. An animal study shows that the expression of the neural crest genes Sox10 seems to be lower in Sf3b4-depleted Xenopus embryos rescued with mRNA containing human frameshift mutation in exon 2 (c.88delT) than a nonsense mutation in exon3 (c.625C 4 T).²⁵ Additionally, a study confirmed that depletion of SF3B4 is not only influenced the neural crest formation but also otic development by modulating the expression of several genes responsible for pan-placodal (eg six1, dmrta1, and foxi4.1) and otic vesicle development (eg pax8, tbx2, otx2, bmp4, and wnt3a).²⁶ Despite the fact that limb anomalies are considered as a typical characteristic of NS, a broader phenotypic spectrum associated with SF3B4 variants has been identified, as such patient harboring substitution variant (c.1168C > T) displays without any limb defects,²⁴ implying a phenotypic expansion of SF3B4 variant. Therefore, according to the above reasons, it is possible to speculate that craniofacial, otic, as well as extremities development, may be greatly affected in patients with frameshift variants. Indeed, frameshift mutations are considered harmful and among the most deleterious changes to the coding sequence of a protein.²⁷

In line with previous findings,^4,11 our observation strengthens the notion that variants within SF3B4 gene that are predicted to lead to NMD of the transcript could result in more severe acrofacial dysostosis phenotypes. This may be explained by the large degraded mutant transcript of patients with NMD. As a consequence, the small amount of abnormal SAP49 protein produced by the cells may alter the splicing function, although the mechanism remains unclear. Indeed, spliceosome is not only essential in modulating intron splicing but is also a key mediator of alternative splicing.²⁸ And thus, the clinical variability observed across NS cases could be a result of the aberrant splicing of genes involved in craniofacial and limb development.

On the other hand, there are no distinctive clinical signs between NS individuals with or without SF3B4 variants. Notably, some of the patients without SF3B4 pathogenic variants exhibited variants in EFTUD2,^3,4 VWA1, and PYGO2.^14,16 Thus, it is possible to hypothesize that other spliceosomal proteins may be involved in the pathogenesis of NS. Further studies with broader genetic testing and larger patient numbers are therefore necessary to fully identify the genetic causes of the disease; while the implementation of model organisms for biological experiments could help us to understand the pathogenesis of NS in the future.

Limitations

Several limitations were identified in this study. First, many of the reported cases did not provide any mutational analysis and complete clinical data. Second, publication bias may be present due to cases with more severe characteristics being commonly published. Thirdly, there is a subjective report regarding clinical manifestations in each of the included studies. Despite said limitations, our study pinpoints that patients with frameshift SF3B4 variants, and predicted to lead to NMD of the transcripts tended to have more severe clinical manifestations observed in NS.

Supplemental Material

sj-xlsx-1-cpc-10.1177_10556656221089156 - Supplemental material for SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome

Supplemental material, sj-xlsx-1-cpc-10.1177_10556656221089156 for SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome by Zulvikar Syambani Ulhaq, Gita Vita Soraya, Lola Ayu Istifiani, Syafrizal Aji Pamungkas and William Ka Fai Tse in The Cleft Palate Craniofacial Journal

Supplemental Material

sj-docx-2-cpc-10.1177_10556656221089156 - Supplemental material for SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome

Supplemental material, sj-docx-2-cpc-10.1177_10556656221089156 for SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome by Zulvikar Syambani Ulhaq, Gita Vita Soraya, Lola Ayu Istifiani, Syafrizal Aji Pamungkas and William Ka Fai Tse in The Cleft Palate Craniofacial Journal

Footnotes

Author’s Contribution

Conceived the study: Z.S.U., W.K.F.T.; Collected the data: Z.S.U., L.A.I., S.A.P.; Performed the analysis: Z.S.U., G.V.S., L.A.I., S.A.P.; Wrote the paper: Z.S.U., G.V.S., W.K.F.T.; Supervision: W.K.F.T.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval

Ethical approval and permission are not required because this study includes no confidential personal data and patient interventions. This study is a meta-analysis based on published eligible studies of genotypic and phenotypic findings in Nager syndrome patients.

Supplemental Material

Supplemental material for this article is available online.

ORCID iD

Zulvikar Syambani Ulhaq

References

Drozniewska

Kilby

Vogt

Togneri

Quinlan-Jones

Reali

Allen

McMullan

(2020) Second-trimester prenatal diagnosis of Nager syndrome with a deletion including SF3B4 detected by chromosomal microarray. Clin Case Rep. 8(3):508‐511. https://doi.org/10.1002/ccr3.2509

Cassina

Cerqua

Rossi

Salviati

Martini

Clementi

Trevisson

(2017) A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome. Eur J Hum Genet EJHG. 25(3):371‐375. https://doi.org/10.1038/ejhg.2016.176

Czeschik

Voigt

Alanay

Albrecht

Avci

FitzPatrick

Goudie

Hehr

Hoogeboom

Kayserili

, et al. (2013) Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. Hum Genet. 132(8):885‐898. https://doi.org/10.1007/s00439-013-1295-2

Bernier

Caluseriu

Schwartzentruber

Buckingham

Innes

Jabs

Innis

Schuette

Gorski

, et al. (2012) Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet. 90(5):925‐933. https://doi.org/10.1016/j.ajhg.2012.04.004

Petit

Escande

Jourdain

Porchet

Amiel

Doray

Delrue

Flori

Kim

Marlin

, et al. (2014) Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause. Clin Genet. 86(3):246‐251. https://doi.org/10.1111/cge.12259

Denu

Burkard

(2017) Synchronous bilateral breast cancer in a patient with Nager syndrome. Clin Breast Cancer. 17(3):e151‐e153. https://doi.org/10.1016/j.clbc.2016.12.009

Drivas

Taylor

Zackai

(2019) The final demise of Rodriguez lethal acrofacial dysostosis: a case report and review of the literature. Am J Med Genet A. 179(6):1063‐1068. https://doi.org/10.1002/ajmg.a.61121

Chummun

McLean

Anderson

van Nieuwenhoven

Mathijssen

David

(2016) The craniofacial and upper limb management of Nager syndrome. J Craniofac Surg. 27(4):932‐937. https://doi.org/10.1097/SCS.0000000000002626

Castori

Bottillo

D’Angelantonio

Morlino

De Bernardo

Scassellati Sforzolini

Silvestri

Grammatico

(2014) A 22-week-old Fetus with Nager syndrome and congenital diaphragmatic hernia due to a novel SF3B4 mutation. Mol Syndromol. 5(5):241‐244. https://doi.org/10.1159/000365769

10.

Hayata

Masuyama

Eto

, et al. (2019) A case of Nager syndrome diagnosed before birth. Acta Med Okayama. 73(3):273‐277. https://doi.org/10.18926/AMO/56872

11.

Marques

Tenney

Duran

Martin

Nevarez

Pogue

Krakow

Cohn

Bateman

(2016) Altered mRNA splicing, chondrocyte gene expression and abnormal skeletal development due to SF3B4 mutations in Rodriguez acrofacial dysostosis. PLoS Genet. 12(9):e1006307. https://doi.org/10.1371/journal.pgen.1006307

12.

Zhao

Yang

(2020) Broad-spectrum next-generation sequencing-based diagnosis of a case of Nager syndrome. J Clin Lab Anal. 34(9):e23426. https://doi.org/10.1002/jcla.23426

13.

Waggoner

Ciske

Dowton

Watson

(1999) Deletion of 1q in a patient with acrofacial dysostosis. Am J Med Genet. 82(4):301‐304. https://doi.org/10.1002/(sici)1096-8628(19990212)82:4<301::aid-ajmg5>3.0.co;2-j

14.

Zhang

Dai

Liu

Ren

(2010) Mandibulofacial dysostosis, microtia, and limb anomalies in a newborn: a new form of acrofacial dysostosis syndrome? Clin Genet. 78:570‐574. https://doi.org/10.1111/j.1399-0004.2010.01427.x

15.

Bellanger

Villedieu

Gerard

Guillois

(2015) Nager syndrome associated with tetralogy of Fallot: a frequent association? Arch Pediatr Organe Off Soc Francaise Pediatr. 22(6):974‐977. https://doi.org/10.1016/j.arcped.2015.06.002

16.

Lin

J-L

(2012) Nager syndrome: a case report. Pediatr Neonatol. 53(2):147‐150. https://doi.org/10.1016/j.pedneo.2012.01.014

17.

Nur

Bernier

Oztekin

Kardelen

Kalay

Parboosingh

Mihci

(2013) Possible autosomal recessive inheritance in an infant with acrofacial dysostosis similar to Nager syndrome. Am J Med Genet A. 161A(9):2311‐2315. https://doi.org/10.1002/ajmg.a.36051

18.

Lund

ICB

Vestergaard

Christensen

Uldbjerg

Becher

(2016) Prenatal diagnosis of Nager syndrome in a 12-week-old fetus with a whole gene deletion of SF3B4 by chromosomal microarray. Eur J Med Genet. 59(1):48‐51. https://doi.org/10.1016/j.ejmg.2015.12.001

19.

Ansart-Franquet

Houfflin-Debarge

Ghoumid

Pasz

Devisme

Manouvrier-Hanu

Andrieux

Holder-Espinasse

(2009) Prenatal diagnosis of Nager syndrome in a monochorionic-diamniotic twin pregnancy. Prenat Diagn. 29(2):187‐189. https://doi.org/10.1002/pd.2214

20.

Pengelly

Upstill-Goddard

Arias

Martinez

Gibson

Knut

Collins

Ennis

Collins

Briceno

(2015) Resolving clinical diagnoses for syndromic cleft lip and/or palate phenotypes using whole-exome sequencing. Clin Genet. 88(5):441‐449. https://doi.org/10.1111/cge.12547

21.

Irving

Dimitrov

Wessels

Holder-Espinasse

Chitayat

Simpson

(2016) Rodriguez acrofacial dysostosis is caused by apparently de novo heterozygous mutations in the SF3B4 gene. Am J Med Genet A. 170(12):3133‐3137. https://doi.org/10.1002/ajmg.a.37946

22.

McPherson

Zaleski

Lin

(2014) Rodriguez syndrome with SF3B4 mutation: a severe form of Nager syndrome? Am J Med Genet A. 164A(7):1841‐1845. https://doi.org/10.1002/ajmg.a.36555

23.

Scapoli

Martinelli

Pezzetti

Carahelli

Carinci

Cenzi

Meneghetti

Donti

(2003) Spontaneous expression of FRA3P in a patient with Nager syndrome. Am J Med Genet A. 118A(3):293‐295. https://doi.org/10.1002/ajmg.a.10258

24.

Cadieux-Dion

Hughes

Engleman

Rush

Saunders

(2021) Nager syndrome in patient lacking acrofacial dysostosis: expanding the phenotypic spectrum of SF3B4-related disease. Am J Med Genet A. 185:1515‐1518. https://doi.org/10.1002/ajmg.a.62113

25.

Devotta

Juraver-Geslin

Gonzalez

Hong

C-S

Saint-Jeannet

J-P

(2016) Sf3b4-depleted Xenopus embryos: a model to study the pathogenesis of craniofacial defects in Nager syndrome. Dev Biol. 415(5):371‐382. https://doi.org/10.1016/j.ydbio.2016.02.010

26.

Maharana

Saint-Jeannet

J-P

(2021) Molecular mechanisms of hearing loss in Nager syndrome. Dev Biol. 476:200‐208. https://doi.org/10.1016/j.ydbio.2021.04.002

27.

Wang

Dong

Chen

, et al. (2019) Frameshifts and wild-type protein sequences are always similar because the genetic code is nearly optimal for frameshift tolerance. bioRxiv 067736, https://doi.org/10.1101/067736

28.

Blaustein

Pelisch

Srebrow

(2007) Signals, pathways and splicing regulation. Int J Biochem Cell Biol. 39(11):2031‐2048. https://doi.org/10.1016/j.biocel.2007.04.004

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