- Email: [email protected]
Fraser syndrome without cryptophthalmos: Two cases
Journal Pre-proof Fraser syndrome without cryptophthalmos: Two cases S. Boussion, S. Lyonnet, B. Van Der Zwaag, M.J. Vogel, T. Smol, A. Mezel, S. Manouvrier-Hanu, C. Vincent-Delorme, C. Vanlerberghe PII:
S1769-7212(19)30148-X
DOI:
https://doi.org/10.1016/j.ejmg.2020.103839
Reference:
EJMG 103839
To appear in:
European Journal of Medical Genetics
Received Date: 27 February 2019 Revised Date:
21 November 2019
Accepted Date: 5 January 2020
Please cite this article as: S. Boussion, S. Lyonnet, B. Van Der Zwaag, M.J. Vogel, T. Smol, A. Mezel, S. Manouvrier-Hanu, C. Vincent-Delorme, C. Vanlerberghe, Fraser syndrome without cryptophthalmos: Two cases, European Journal of Medical Genetics (2020), doi: https://doi.org/10.1016/ j.ejmg.2020.103839. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Masson SAS.
Credit Authors Statement
Simon Boussion: Writing – Original Draft Stanislas Lyonnet: Investigation, Writing – Review & Editing Bert Van der Zwaag: Resources, Validation, Data Curation M.J. Vogel: Resources, Validation, Data Curation Thomas Smol: Formal Analysis, Data Curation Aurélie Mézel: Writing – Review & Editing Sylvie Manouvrier-Hanu: Writing – Review & Editing Catherine Vincent-Delorme: Investigation, Writing – Review & Editing Clémence Vanlerberghe: Writing – Review & Editing, Supervision, Project Administration
Fraser syndrome without cryptophthalmos: two cases.
S. BOUSSION1,2, S. LYONNET3, B. VAN DER ZWAAG4, M.J. VOGEL4, T. SMOL2,5, A. MEZEL6, S. MANOUVRIER-HANU1,2, C. VINCENT-DELORME1,2, C. VANLERBERGHE1,2
1
CHU Lille, Clinique de Génétique, F-59000 Lille, France
2
Univ. Lille, RADEME, EA 7364, F-59000 Lille, France
3
Service de Génétique Médicale et Institut Imagine, Inserm UMR1163, Hôpital universitaire Necker-
Enfants malades, AP-HP, Paris, France 4
Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
5
CHU Lille, Institut de Génétique Médicale, F-59000 Lille, France
6
CHU Lille, Service de chirurgie orthopédique pédiatrique, F-59000 Lille, France
Corresponding author : Clémence VANLERBERGHE Clinique de Génétique Médicale CHU Lille 59037 LILLE Cedex Tel +33.3.20.44.49.11 Fax +33.3.20.44.49.01 [email protected]
The authors declare no conflict of interest.
1
ABSTRACT Fraser syndrome (MIM#219000) is an autosomal recessive disorder, characterized by the association of cryptophthtalmos, syndactyly of the four extremities, urinary tract abnormalities and laryngotracheal anomalies. This condition is due to homozygous or compound heterozygous mutations in the FRAS/FREM complex genes: FRAS1, FREM2 and GRIP1. Here we report two atypical cases of Fraser syndrome due to mutations in the FRAS1 gene without cryptophthalmos. The first proband had syndactyly of three extremities, bilateral nostril coloboma, dysplastic ears with bilateral conductive hearing loss, blepharophimosis and lacrimal duct abnormalities. FRAS1 sequencing identified two pathogenic compound heterozygous variants: a nonsense variant in exon 70 and a missense variant in exon 24. The second proband had membranous syndactyly of the four extremities, left renal agenesis, laryngeal and ano-rectal malformations, dysplastic ears and bilateral conductive hearing loss. FRAS1 sequencing identified a pathogenic homozygous variant in the last exon of the gene. This first description of molecularly confirmed cases with Fraser syndrome without cryptophthalmos could contribute to further delineation of the clinical spectrum of Fraser syndrome, especially for possible phenotypically milder cases. Larger cohorts are required to try to refer the hypothesis of genotype-phenotype correlation.
INTRODUCTION Fraser syndrome (MIM#219000) is a rare autosomal recessive malformative disorder, characterized by cryptophthalmos, membranous syndactyly of the four extremities, urogenital, renal and laryngeal anomalies(Fraser, 1962). Its prevalence is 0,2/100.000 births, and more than 300 cases have been reported so far(Barisic et al., 2013). Diagnostic criteria have been defined in 2007. The major criteria are the presence of syndactyly, cryptophthalmos spectrum features, urinary tract abnormalities, ambiguous genitalia, laryngeal and/or tracheal anomalies or positive family history of Fraser syndrome. The minor criteria are the presence of anorectal defects, dysplastic ears, nasal anomalies,
2
skull ossification defects or umbilical cord abnormalities(van Haelst et al., 2007). The clinical diagnosis of Fraser syndrome can be affirmed in the presence of 3 major features, or 2 major features and 2 minor features, or 1 major feature and 3 minor features(van Haelst et al., 2007). Cryptophthalmos and syndactyly seem to be the most constant features of this disorder, cryptophthalmos being the most defining feature of Fraser syndrome(Barisic et al., 2013; Gattuso et al., 1987; Slavotinek and Tifft, 2002; Thomas et al., 1986; van Haelst et al., 2007). A wide variability of expression has been observed, making its clinical diagnosis sometimes challenging. Fraser syndrome is a genetically heterogeneous disorder. Three genes are known to be involved in this condition: FRAS1 (MIM#607830) on 4q21.21(McGregor et al., 2003) GRIP1 (MIM#604597) on 12q14.3(Vogel et al., 2012, p. 1) (and FREM2 (MIM#608945) on 13q13.3(Jadeja et al., 2005). In patients that meet the diagnostic criteria a mutation detection rate of approximately 50% is achieved(van Haelst et al., 2007), with the majority of cases showing pathogenic mutations in the FRAS1 gene (~75%)(Hoefele et al., 2013). Nevertheless, establishing a clear genotype-phenotype correlation has proven difficult so far. Here we report two cases of mild presentation of Fraser syndrome, without cryptophthalmos, clinically suspected and confirmed by the presence of FRAS1 mutations. We discuss the clinical heterogeneity of this disorder and the hypothesis of phenotype-genotype correlation.
METHODS Patients Two patients presenting with multiple malformations were referred to a clinical genetics department Our study was performed using the Declaration of Helsinki protocol. Written informed consents were obtained from the patients or their parents prior to the molecular diagnostic analysis. Molecular analysis Peripheral blood was collected from patients and their parents. Karyotype was performed according standard procedures. 60K array-Comparative Genomic Hybridization (CGH) (Human genome CGH
3
TM
microarray 60B kit Agilent ) was used to detect pangenomic copy number variations, according to the manufacturer’s protocol. Mutation screening of the FRAS1 gene in patient 1 was performed at the ISO15189 accredited Genome diagnostics section of the UMC Utrecht department of Genetics in 2010. In short, mutation screening of protein coding exons and flanking intronic regions was performed by amplification followed by sequencing on a Roche 454 Genome Sequencer FLX system. The detected mutations were subsequently confirmed using direct Sanger sequencing. In patient 2, Sanger sequencing of all protein coding exons and flanking intronic regions of the FAM58A (MIM#300708) and SALL1 (MIM#602218) gene was first performed. Subsequently mutation analysis of all protein coding exons and flanking intronic regions of Fraser syndrome associated genes was performed at the Genome diagnostics section of the UMC Utrecht department of Genetics. In short, all protein coding exons of the three genes known to be involved in Fraser syndrome (FRAS1, FREM2, GRIP1) and the FREM1 gene (MIM#608944), involved in MOTA syndrome (Manitoba-oculo-trichoanal syndrome, MIM#288450) were enriched by a custom designed Agilent SureSelectXT capture probe set followed by single end short read (50 bp) sequencing on a Life Technologies/Applied Biosystems SOLiD 5500XL Genetic Analyzer to an average depth of >100X. Minimal horizontal coverage of the individual genes was >15X for >99% of the targeted sequence. The detected mutations were subsequently confirmed using direct Sanger sequencing. FRAS1 mutations are given according to reference sequence NM_025074.6 (Hg19).
RESULTS Patient 1 The first proband was the first child of a non-consanguineous couple, without relevant family history. She was born at term after an unremarkable pregnancy. Birth growth parameters were normal. She presented with abnormalities in the extremities, consisting in partial I-II and complete II-V feet membranous syndactyly, partial I-II membranous syndactyly of the right hand with a large space between the second and third rays (Figure 1D-E). Left hand was normal. She presented discrete
4
genital anomalies: increased spacing of the superior part of labia minora, abnormal folding of labia majora. Dysmorphic features were observed: small and dysplastic ears (ear lobe hypoplasia), partial and symmetrical coloboma of both nostrils (Figure 1A-C). Ophthalmologic assessment showed moderate blepharophimosis and lacrymal canals defects, but no cryptophthalmos or microphthalmia. Visual tests, slit-lamp examination and fundus examination were normal. ENT investigations showed moderate conductive hearing loss. Hand and feet X-rays were normal. She grew up with normal motor milestones, but with a speech delay, due to hearing impairment. Growth parameters remained in the average at 3 years old. Standard karyotyping was normal. Mutation screening of the FRAS1 gene revealed compound heterozygosity for two pathogenic variants: a nonsense variant, NM_025074.7: c.10820C>G; p.(Ser3607*), in exon 70, inherited from the mother, and a missense variant, NM_025074.7: c.2894G>T; p.(Cys965Phe), in exon 24, inherited from the father. These variants were not reported in the population databases dbSNP (build151), ExAC and GnomAD. Pathogenic variants have not been reported at these positions. Both variants have been submitted to ClinVar database (VCV000633615.1 and VCV000633785.1). The nonsense variant NM_025074.7:c.10820C>G;p.(Ser3607*) is pathogenic according ACMG Classification of Sequence Variants criteria (class 5). The missense variant NM_025074.7: c.2894G>T; p.(Cys965Phe) affects a highly conserved amino acid in a furin-like repeat domain of the FRAS1 protein (which is involved in a mechanism of signal transduction), represents a very large physicochemical difference and is predicted to be pathogenic by multiple mutation interpretation prediction tools (SIFT, Polyphen-2, Mutation Taster PROVEAN). It is considered as a likely pathogenic variant according ACMG Classification of Sequence Variants criteria (class 4). These results confirmed the diagnosis of Fraser syndrome.
Patient 2
5
The second proband was the first child of non-consanguineous couple. Parents’ families come from neighboring villages in Morocco. Left renal agenesis, right renal ectopia and oligohydramnios were observed at 16 weeks of amenorrhea. The parents refused further investigations during pregnancy. The proband was born at 35 weeks of gestation. Growth parameters, taking into account the prematurity, were in the average. She presented with multiple malformations: intrauterine growth retardation, II-V membranous syndactyly of the four extremities (Figure 1F-G), clitoromegaly, cloaca, anal atresia and moderate facial dysmorphic features (telecanthus, microstomia, dysplastic ears). Abdominal ultrasound confirmed the renal malformation suspected during the pregnancy. Genital explorations revealed vaginal atresia and rectovaginal fistula. ENT assessment showed bilateral moderate hearing loss (air conduction 70dB, bone conduction 20dB), due to ear canal stenosis and complete filling of middle ears at CT scan. Inner ear MRI showed no abnormality. Laryngotracheal fibroscopy showed hypoplasia of ventricular bands of larynx, impeding the phonation. Ophtalmologic assessment was completely normal. Whole skeleton radiographs and cardiac ultrasounds at birth were normal. She grew up with normal motor milestones, but with a speech delay, due to hearing impairment. At 3 years-old, height and weight were at -2SD, and head circumference was at 0SD. Array-CGH analysis did not reveal larger genomic aberrations. Sanger sequencing of FAM58A and SALL1 in the hypothesis of, respectively, STAR syndrome (MIM#300707) and Townes-Brocks syndrome (MIM#107480), were normal. Next Generation Sequencing of the three genes known to be associated with Fraser syndrome (FRAS1, FREM2, GRIP1) and FREM1 gene (implied in MOTA syndrome, a syndromic entity close to Fraser syndrome) revealed a homozygous frameshift variant in the very last exon of FRAS1 gene: NM_025074.7: c.11897dup; p.(Asn3967Glufs*2). This variant was not reported in the population databases dbSNP (build151), ExAC and GnomAD. Pathogenic variants have not been reported at this position. This variant has been submitted to ClinVar database (VCV000633784.1). This variant is predicted to result in a truncated FRAS1 protein and is considered as a pathogenic variant according ACMG Classification of Sequence Variants criteria (class 5). Both
6
parents were heterozygous for this variant. These results confirmed the diagnosis of Fraser syndrome.
DISCUSSION Here we describe two mild presentations of Fraser syndrome with FRAS1 mutations, but without cryptophthalmos. In the current paper, both patients met the diagnosis criteria proposed by van Haelst et al (van Haelst et al., 2007). In this algorithm, the major criteria « ocular anomalies » is not limited to cryptophthalmos, so that these patients fulfilled 2 major criteria and 2 minor criteria. Cryptophthalmos is the most common feature of Fraser syndrome, along with syndactyly. In the previously described cohorts including more than 300 cases, cryptophthalmos was observed in 85 to 93% of the patients (Gattuso et al., 1987; Slavotinek and Tifft, 2002; Thomas et al., 1986; van Haelst et al., 2007). Whereas the association of cryptophthalmos, syndactyly and urogenital malformations is highly specific of Fraser syndrome, cryptophthalmos is not mandatory in Fraser syndrome. In the literature, four cases of Fraser syndrome without cryptophthalmos have been described but no options for molecular confirmation were available at that time (Burn and Marwood, 1982; Koenig and Spranger, 1986; Lurie and Cherstvoy, 1984). Prenatal diagnosis of Fraser syndrome could be difficult. Tessier et al. analyzed the largest cohort of fetal cases of Fraser syndrome ever described (38 cases) and found that major diagnostic criteria, as syndactyly, cryptophthalmos or genital anomalies, are rarely found on prenatal ultrasonography, although they are easily identified on postnatal fetal examination (Tessier et al., 2016). The diagnosis should be considered by the association of CHAOS (Congenital High Airway Obstruction Sequence), oligohydramnios and renal agenesis. None of these features was present in Patient 1. In our patients, the diagnosis was confirmed by the detection of bi-allelic pathogenic FRAS1 mutations: either the association of a missense mutation in the first part of the gene and a nonsense mutation located in the last exons of the gene, or a homozygous frameshift mutation located in the
7
last exon of the gene, likely escaping nonsense mediated decay (NMD) of the mRNA, leading to the loss of the 35 most C-terminal amino acids.
So far, 28 variants have been reported in FRAS1 gene in the databases HGMD and ClinVar, most of them being truncating variants located between exon 5 and exon 71. The rarity of this syndrome and the difficulties of FRAS1 sequencing due its large number of exons hampered establishing phenotypegenotype correlations. The first publication of FRAS1 variants in Fraser syndrome reported four homozygous nonsense variants and one homozygous frameshift variant (resulting in termination of the protein three amino acids later), located between exons 29 and 61 and predicted to cause loss of function but with no correlation between the location of the variant and the phenotype (McGregor et al., 2003). Later publications of Fraser syndrome due to FRAS1 mutations were not comparable to our cases, because of the severity of the phenotype, the presence of cryptophthalmos, and the characteristics of the FRAS1 variants (frameshift variant associated with intragenic deletion (exons 3 to 14) of FRAS1, and compound heterozygous truncating variants in the first exons of FRAS1) (Hoefele et al., 2013; Slavotinek et al., 2006). Recently, Nayak et al. reported familial cases of Fraser syndrome due to homozygous splice site FRAS1 variant (junction intron 26 and exon 27), but the patients had severe and lethal phenotypes (Nayak et al., 2017). Biallelic missense FRAS1 variant were reported in 5 patients presenting with isolated congenital anomalies of the kidneys and urinary tract (CAKUT) (Kohl et al., 2014). One of them had an associated anal atresia. Only one patient harboring a FRAS1 truncating variant in exon 55 and a FRAS1 missense variant in exon 64 has been described in isolated CAKUT.
We describe for the first time novel variants in the FRAS1 gene in patients with Fraser syndrome without cryptophthalmos. These unusual presentations could be due to the characteristics of the FRAS1 variants, either the association of missense and truncating variants, or a homozygous
8
frameshift variant in the last exon of the gene. This hypothesis is supported by the previous observations of CAKUT in patients with biallelic missense FRAS1 variants, and by the fact that most of the previously described patients with typical Fraser syndrome do not harbor FRAS1 variants in the last exons. However, this hypothesis could be questioned by the following facts. First, 3 families with biallelic FRAS1 missense variants have been reported with a Fraser syndrome form with multiple malformations. For 2 families, the homozygous missense variants were located in 3’ exons of the gene (exon 63 and exon 65 respectively), outside of any known functional domains(van Haelst et al., 2008). The last patient carried compound heterozygous missense variants, one located in a furin-like domain, another in the last exons of the gene (exon 74), outside of any known functional domain (Ng et al., 2013). Furthermore, variants reported in CAKUT are localized from c.4159 to c.9959, out of the C-term region. The wide clinical heterogeneity of Fraser syndrome, illustrated with our atypical cases, remains difficult to explain. Description of larger cohorts of FRAS1 mutated patients and functional studies are required to better understand this variability of expression and the consequences of the observed missense mutations.
9
FIGURES/TABLES LEGENDS Table 1 – Phenotypes of our patients compared to the clinical presentation of the patients previously reported in the literature (frequency in %)
Main series of Fraser syndrome patients Our patients Clinical features
Van Haelst et al. (2007)
Slavotinek et al. (2002)
Gattuso et al. (1987)
Thomas et al. (1986)
59
117
68
124
Patient 1
Patient 2
Cryptophthalmos
-
-
85
88
93
85
Membranous syndactyly Genital malformations Urinary tract anomalies
+ + -
+ + +
95 66 80
62 40 49
54 30 37
79 60 80
- bilateral renal agenesis
-
-
36
23
-
58
- unilateral renal agenesis - uni- or bilateral renal hypoplasia - uni- or bilateral ureteral agenesis - bladder anomalies
-
+
41
22
-
33
-
-
15
-
-
10
-
-
10
-
-
-
-
-
17
17
10
-
Airway malformations - laryngeal anomalies
-
+ +
58 49
31
21
83
- tracheal anomalies
-
-
14
+ +
+ -
17 75 29 9 53
34 59 11 11 55
34 44 6 7 37
27 84 11 85
-
+ -
12 5 32 10 7
8 16 12 5
6 6 19
2 6 81
Number of patients
Dysmorphy - abnormal hair line - ear dysplasia - low-set umbilicus - cleft lip and/or palate - nasal anomalies Other malformations - skull ossification defects - meningo-encephalocele - anal atresia/stenosis - congenital heart defects Intellectual disability
10
Figure 1 - Patient 1 (A) Facial appearance at the age of 10 months, showing partial and symmetrical coloboma of both nostrils; (B,C) Small and dysplastic ears, with ear lobe hypoplasia. (D) Feet’s aspect at the age of 10 months, showing partial I-II and complete II-V bilateral membranous syndactyly; (E) Hands’ aspect at the age of 27 months, showing partial I-II membranous syndactyly of the right hand with a large space between the second and third rays; Patient 2 (F) Hands’ aspect in the neonatal period, with II-V bilateral syndactyly; (G) Hand’s aspect after surgery.
11
REFERENCES Barisic, I., Odak, L., Loane, M., Garne, E., Wellesley, D., Calzolari, E., Dolk, H., Addor, M.-C., Arriola, L., Bergman, J., Bianca, S., Boyd, P.A., Draper, E.S., Gatt, M., Haeusler, M., Khoshnood, B., LatosBielenska, A., McDonnell, B., Pierini, A., Rankin, J., Rissmann, A., Queisser-Luft, A., VerellenDumoulin, C., Stone, D., Tenconi, R., 2013. Fraser syndrome: epidemiological study in a European population. Am. J. Med. Genet. A. 161A, 1012–1018. https://doi.org/10.1002/ajmg.a.35839 Burn, J., Marwood, R.P., 1982. Fraser syndrome presenting as bilateral renal agenesis in three sibs. J. Med. Genet. 19, 360–361. Fraser, G.R., 1962. Our genetical ‘load’. A review of some aspects of genetical variation. Ann. Hum. Genet. 25, 387–415. https://doi.org/10.1111/j.1469-1809.1962.tb01774.x Gattuso, J., Patton, M.A., Baraitser, M., 1987. The clinical spectrum of the Fraser syndrome: report of three new cases and review. J. Med. Genet. 24, 549–555. Hoefele, J., Wilhelm, C., Schiesser, M., Mack, R., Heinrich, U., Weber, L.T., Biskup, S., Daumer-Haas, C., Klein, H.-G., Rost, I., 2013. Expanding the mutation spectrum for Fraser syndrome: identification of a novel heterozygous deletion in FRAS1. Gene 520, 194–197. https://doi.org/10.1016/j.gene.2013.02.031 Jadeja, S., Smyth, I., Pitera, J.E., Taylor, M.S., van Haelst, M., Bentley, E., McGregor, L., Hopkins, J., Chalepakis, G., Philip, N., Perez Aytes, A., Watt, F.M., Darling, S.M., Jackson, I., Woolf, A.S., Scambler, P.J., 2005. Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nat. Genet. 37, 520–525. https://doi.org/10.1038/ng1549 Koenig, R., Spranger, J., 1986. Cryptophthalmos--syndactyly syndrome without cryptophthalmos. Clin. Genet. 29, 413–416. Kohl, S., Hwang, D.-Y., Dworschak, G.C., Hilger, A.C., Saisawat, P., Vivante, A., Stajic, N., Bogdanovic, R., Reutter, H.M., Kehinde, E.O., Tasic, V., Hildebrandt, F., 2014. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J. Am. Soc. Nephrol. JASN 25, 1917–1922. https://doi.org/10.1681/ASN.2013101103 Lurie, I.W., Cherstvoy, E.D., 1984. Renal agenesis as a diagnostic feature of the cryptophthalmossyndactyly syndrome. Clin. Genet. 25, 528–532. McGregor, L., Makela, V., Darling, S.M., Vrontou, S., Chalepakis, G., Roberts, C., Smart, N., Rutland, P., Prescott, N., Hopkins, J., Bentley, E., Shaw, A., Roberts, E., Mueller, R., Jadeja, S., Philip, N., Nelson, J., Francannet, C., Perez-Aytes, A., Megarbane, A., Kerr, B., Wainwright, B., Woolf, A.S., Winter, R.M., Scambler, P.J., 2003. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat. Genet. 34, 203–208. https://doi.org/10.1038/ng1142 Nayak, S.S., Salian, S., Shukla, A., Mathew, M., Girisha, K.M., 2017. Variable presentation of Fraser syndrome in two fetuses and a novel mutation in FRAS1. Congenit. Anom. 57, 83–85. https://doi.org/10.1111/cga.12188 Ng, W.Y., Pasutto, F., Bardakjian, T.M., Wilson, M.J., Watson, G., Schneider, A., Mackey, D.A., Grigg, J.R., Zenker, M., Jamieson, R.V., 2013. A puzzle over several decades: eye anomalies with FRAS1 and STRA6 mutations in the same family. Clin. Genet. 83, 162–168. https://doi.org/10.1111/j.1399-0004.2012.01851.x Slavotinek, A., Li, C., Sherr, E.H., Chudley, A.E., 2006. Mutation analysis of the FRAS1 gene demonstrates new mutations in a propositus with Fraser syndrome. Am. J. Med. Genet. A. 140, 1909–1914. https://doi.org/10.1002/ajmg.a.31399 Slavotinek, A.M., Tifft, C.J., 2002. Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J. Med. Genet. 39, 623–633. Tessier, A., Sarreau, M., Pelluard, F., André, G., Blesson, S., Bucourt, M., Dechelotte, P., Faivre, L., Frébourg, T., Goldenberg, A., Goua, V., Jeanne-Pasquier, C., Guimiot, F., Laquerriere, A.,
12
Laurent, N., Lefebvre, M., Loget, P., Maréchaud, M., Mechler, C., Perez, M.-J., Sabourin, J.C., Verloes, A., Patrier, S., Guerrot, A.-M., 2016. Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases. Prenat. Diagn. 36, 1270–1275. https://doi.org/10.1002/pd.4971 Thomas, I.T., Frias, J.L., Felix, V., Sanchez de Leon, L., Hernandez, R.A., Jones, M.C., 1986. Isolated and syndromic cryptophthalmos. Am. J. Med. Genet. 25, 85–98. https://doi.org/10.1002/ajmg.1320250111 van Haelst, M.M., Maiburg, M., Baujat, G., Jadeja, S., Monti, E., Bland, E., Pearce, K., Fraser Syndrome Collaboration Group, Hennekam, R.C., Scambler, P.J., 2008. Molecular study of 33 families with Fraser syndrome new data and mutation review. Am. J. Med. Genet. A. 146A, 2252– 2257. https://doi.org/10.1002/ajmg.a.32440 van Haelst, M.M., Scambler, P.J., Fraser Syndrome Collaboration Group, Hennekam, R.C.M., 2007. Fraser syndrome: a clinical study of 59 cases and evaluation of diagnostic criteria. Am. J. Med. Genet. A. 143A, 3194–3203. https://doi.org/10.1002/ajmg.a.31951 Vogel, M.J., van Zon, P., Brueton, L., Gijzen, M., van Tuil, M.C., Cox, P., Schanze, D., Kariminejad, A., Ghaderi-Sohi, S., Blair, E., Zenker, M., Scambler, P.J., Ploos van Amstel, H.K., van Haelst, M.M., 2012. Mutations in GRIP1 cause Fraser syndrome. J. Med. Genet. 49, 303–306. https://doi.org/10.1136/jmedgenet-2011-100590
13
S1769-7212(19)30148-X
DOI:
https://doi.org/10.1016/j.ejmg.2020.103839
Reference:
EJMG 103839
To appear in:
European Journal of Medical Genetics
Received Date: 27 February 2019 Revised Date:
21 November 2019
Accepted Date: 5 January 2020
Please cite this article as: S. Boussion, S. Lyonnet, B. Van Der Zwaag, M.J. Vogel, T. Smol, A. Mezel, S. Manouvrier-Hanu, C. Vincent-Delorme, C. Vanlerberghe, Fraser syndrome without cryptophthalmos: Two cases, European Journal of Medical Genetics (2020), doi: https://doi.org/10.1016/ j.ejmg.2020.103839. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Masson SAS.
Credit Authors Statement
Simon Boussion: Writing – Original Draft Stanislas Lyonnet: Investigation, Writing – Review & Editing Bert Van der Zwaag: Resources, Validation, Data Curation M.J. Vogel: Resources, Validation, Data Curation Thomas Smol: Formal Analysis, Data Curation Aurélie Mézel: Writing – Review & Editing Sylvie Manouvrier-Hanu: Writing – Review & Editing Catherine Vincent-Delorme: Investigation, Writing – Review & Editing Clémence Vanlerberghe: Writing – Review & Editing, Supervision, Project Administration
Fraser syndrome without cryptophthalmos: two cases.
S. BOUSSION1,2, S. LYONNET3, B. VAN DER ZWAAG4, M.J. VOGEL4, T. SMOL2,5, A. MEZEL6, S. MANOUVRIER-HANU1,2, C. VINCENT-DELORME1,2, C. VANLERBERGHE1,2
1
CHU Lille, Clinique de Génétique, F-59000 Lille, France
2
Univ. Lille, RADEME, EA 7364, F-59000 Lille, France
3
Service de Génétique Médicale et Institut Imagine, Inserm UMR1163, Hôpital universitaire Necker-
Enfants malades, AP-HP, Paris, France 4
Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
5
CHU Lille, Institut de Génétique Médicale, F-59000 Lille, France
6
CHU Lille, Service de chirurgie orthopédique pédiatrique, F-59000 Lille, France
Corresponding author : Clémence VANLERBERGHE Clinique de Génétique Médicale CHU Lille 59037 LILLE Cedex Tel +33.3.20.44.49.11 Fax +33.3.20.44.49.01 [email protected]
The authors declare no conflict of interest.
1
ABSTRACT Fraser syndrome (MIM#219000) is an autosomal recessive disorder, characterized by the association of cryptophthtalmos, syndactyly of the four extremities, urinary tract abnormalities and laryngotracheal anomalies. This condition is due to homozygous or compound heterozygous mutations in the FRAS/FREM complex genes: FRAS1, FREM2 and GRIP1. Here we report two atypical cases of Fraser syndrome due to mutations in the FRAS1 gene without cryptophthalmos. The first proband had syndactyly of three extremities, bilateral nostril coloboma, dysplastic ears with bilateral conductive hearing loss, blepharophimosis and lacrimal duct abnormalities. FRAS1 sequencing identified two pathogenic compound heterozygous variants: a nonsense variant in exon 70 and a missense variant in exon 24. The second proband had membranous syndactyly of the four extremities, left renal agenesis, laryngeal and ano-rectal malformations, dysplastic ears and bilateral conductive hearing loss. FRAS1 sequencing identified a pathogenic homozygous variant in the last exon of the gene. This first description of molecularly confirmed cases with Fraser syndrome without cryptophthalmos could contribute to further delineation of the clinical spectrum of Fraser syndrome, especially for possible phenotypically milder cases. Larger cohorts are required to try to refer the hypothesis of genotype-phenotype correlation.
INTRODUCTION Fraser syndrome (MIM#219000) is a rare autosomal recessive malformative disorder, characterized by cryptophthalmos, membranous syndactyly of the four extremities, urogenital, renal and laryngeal anomalies(Fraser, 1962). Its prevalence is 0,2/100.000 births, and more than 300 cases have been reported so far(Barisic et al., 2013). Diagnostic criteria have been defined in 2007. The major criteria are the presence of syndactyly, cryptophthalmos spectrum features, urinary tract abnormalities, ambiguous genitalia, laryngeal and/or tracheal anomalies or positive family history of Fraser syndrome. The minor criteria are the presence of anorectal defects, dysplastic ears, nasal anomalies,
2
skull ossification defects or umbilical cord abnormalities(van Haelst et al., 2007). The clinical diagnosis of Fraser syndrome can be affirmed in the presence of 3 major features, or 2 major features and 2 minor features, or 1 major feature and 3 minor features(van Haelst et al., 2007). Cryptophthalmos and syndactyly seem to be the most constant features of this disorder, cryptophthalmos being the most defining feature of Fraser syndrome(Barisic et al., 2013; Gattuso et al., 1987; Slavotinek and Tifft, 2002; Thomas et al., 1986; van Haelst et al., 2007). A wide variability of expression has been observed, making its clinical diagnosis sometimes challenging. Fraser syndrome is a genetically heterogeneous disorder. Three genes are known to be involved in this condition: FRAS1 (MIM#607830) on 4q21.21(McGregor et al., 2003) GRIP1 (MIM#604597) on 12q14.3(Vogel et al., 2012, p. 1) (and FREM2 (MIM#608945) on 13q13.3(Jadeja et al., 2005). In patients that meet the diagnostic criteria a mutation detection rate of approximately 50% is achieved(van Haelst et al., 2007), with the majority of cases showing pathogenic mutations in the FRAS1 gene (~75%)(Hoefele et al., 2013). Nevertheless, establishing a clear genotype-phenotype correlation has proven difficult so far. Here we report two cases of mild presentation of Fraser syndrome, without cryptophthalmos, clinically suspected and confirmed by the presence of FRAS1 mutations. We discuss the clinical heterogeneity of this disorder and the hypothesis of phenotype-genotype correlation.
METHODS Patients Two patients presenting with multiple malformations were referred to a clinical genetics department Our study was performed using the Declaration of Helsinki protocol. Written informed consents were obtained from the patients or their parents prior to the molecular diagnostic analysis. Molecular analysis Peripheral blood was collected from patients and their parents. Karyotype was performed according standard procedures. 60K array-Comparative Genomic Hybridization (CGH) (Human genome CGH
3
TM
microarray 60B kit Agilent ) was used to detect pangenomic copy number variations, according to the manufacturer’s protocol. Mutation screening of the FRAS1 gene in patient 1 was performed at the ISO15189 accredited Genome diagnostics section of the UMC Utrecht department of Genetics in 2010. In short, mutation screening of protein coding exons and flanking intronic regions was performed by amplification followed by sequencing on a Roche 454 Genome Sequencer FLX system. The detected mutations were subsequently confirmed using direct Sanger sequencing. In patient 2, Sanger sequencing of all protein coding exons and flanking intronic regions of the FAM58A (MIM#300708) and SALL1 (MIM#602218) gene was first performed. Subsequently mutation analysis of all protein coding exons and flanking intronic regions of Fraser syndrome associated genes was performed at the Genome diagnostics section of the UMC Utrecht department of Genetics. In short, all protein coding exons of the three genes known to be involved in Fraser syndrome (FRAS1, FREM2, GRIP1) and the FREM1 gene (MIM#608944), involved in MOTA syndrome (Manitoba-oculo-trichoanal syndrome, MIM#288450) were enriched by a custom designed Agilent SureSelectXT capture probe set followed by single end short read (50 bp) sequencing on a Life Technologies/Applied Biosystems SOLiD 5500XL Genetic Analyzer to an average depth of >100X. Minimal horizontal coverage of the individual genes was >15X for >99% of the targeted sequence. The detected mutations were subsequently confirmed using direct Sanger sequencing. FRAS1 mutations are given according to reference sequence NM_025074.6 (Hg19).
RESULTS Patient 1 The first proband was the first child of a non-consanguineous couple, without relevant family history. She was born at term after an unremarkable pregnancy. Birth growth parameters were normal. She presented with abnormalities in the extremities, consisting in partial I-II and complete II-V feet membranous syndactyly, partial I-II membranous syndactyly of the right hand with a large space between the second and third rays (Figure 1D-E). Left hand was normal. She presented discrete
4
genital anomalies: increased spacing of the superior part of labia minora, abnormal folding of labia majora. Dysmorphic features were observed: small and dysplastic ears (ear lobe hypoplasia), partial and symmetrical coloboma of both nostrils (Figure 1A-C). Ophthalmologic assessment showed moderate blepharophimosis and lacrymal canals defects, but no cryptophthalmos or microphthalmia. Visual tests, slit-lamp examination and fundus examination were normal. ENT investigations showed moderate conductive hearing loss. Hand and feet X-rays were normal. She grew up with normal motor milestones, but with a speech delay, due to hearing impairment. Growth parameters remained in the average at 3 years old. Standard karyotyping was normal. Mutation screening of the FRAS1 gene revealed compound heterozygosity for two pathogenic variants: a nonsense variant, NM_025074.7: c.10820C>G; p.(Ser3607*), in exon 70, inherited from the mother, and a missense variant, NM_025074.7: c.2894G>T; p.(Cys965Phe), in exon 24, inherited from the father. These variants were not reported in the population databases dbSNP (build151), ExAC and GnomAD. Pathogenic variants have not been reported at these positions. Both variants have been submitted to ClinVar database (VCV000633615.1 and VCV000633785.1). The nonsense variant NM_025074.7:c.10820C>G;p.(Ser3607*) is pathogenic according ACMG Classification of Sequence Variants criteria (class 5). The missense variant NM_025074.7: c.2894G>T; p.(Cys965Phe) affects a highly conserved amino acid in a furin-like repeat domain of the FRAS1 protein (which is involved in a mechanism of signal transduction), represents a very large physicochemical difference and is predicted to be pathogenic by multiple mutation interpretation prediction tools (SIFT, Polyphen-2, Mutation Taster PROVEAN). It is considered as a likely pathogenic variant according ACMG Classification of Sequence Variants criteria (class 4). These results confirmed the diagnosis of Fraser syndrome.
Patient 2
5
The second proband was the first child of non-consanguineous couple. Parents’ families come from neighboring villages in Morocco. Left renal agenesis, right renal ectopia and oligohydramnios were observed at 16 weeks of amenorrhea. The parents refused further investigations during pregnancy. The proband was born at 35 weeks of gestation. Growth parameters, taking into account the prematurity, were in the average. She presented with multiple malformations: intrauterine growth retardation, II-V membranous syndactyly of the four extremities (Figure 1F-G), clitoromegaly, cloaca, anal atresia and moderate facial dysmorphic features (telecanthus, microstomia, dysplastic ears). Abdominal ultrasound confirmed the renal malformation suspected during the pregnancy. Genital explorations revealed vaginal atresia and rectovaginal fistula. ENT assessment showed bilateral moderate hearing loss (air conduction 70dB, bone conduction 20dB), due to ear canal stenosis and complete filling of middle ears at CT scan. Inner ear MRI showed no abnormality. Laryngotracheal fibroscopy showed hypoplasia of ventricular bands of larynx, impeding the phonation. Ophtalmologic assessment was completely normal. Whole skeleton radiographs and cardiac ultrasounds at birth were normal. She grew up with normal motor milestones, but with a speech delay, due to hearing impairment. At 3 years-old, height and weight were at -2SD, and head circumference was at 0SD. Array-CGH analysis did not reveal larger genomic aberrations. Sanger sequencing of FAM58A and SALL1 in the hypothesis of, respectively, STAR syndrome (MIM#300707) and Townes-Brocks syndrome (MIM#107480), were normal. Next Generation Sequencing of the three genes known to be associated with Fraser syndrome (FRAS1, FREM2, GRIP1) and FREM1 gene (implied in MOTA syndrome, a syndromic entity close to Fraser syndrome) revealed a homozygous frameshift variant in the very last exon of FRAS1 gene: NM_025074.7: c.11897dup; p.(Asn3967Glufs*2). This variant was not reported in the population databases dbSNP (build151), ExAC and GnomAD. Pathogenic variants have not been reported at this position. This variant has been submitted to ClinVar database (VCV000633784.1). This variant is predicted to result in a truncated FRAS1 protein and is considered as a pathogenic variant according ACMG Classification of Sequence Variants criteria (class 5). Both
6
parents were heterozygous for this variant. These results confirmed the diagnosis of Fraser syndrome.
DISCUSSION Here we describe two mild presentations of Fraser syndrome with FRAS1 mutations, but without cryptophthalmos. In the current paper, both patients met the diagnosis criteria proposed by van Haelst et al (van Haelst et al., 2007). In this algorithm, the major criteria « ocular anomalies » is not limited to cryptophthalmos, so that these patients fulfilled 2 major criteria and 2 minor criteria. Cryptophthalmos is the most common feature of Fraser syndrome, along with syndactyly. In the previously described cohorts including more than 300 cases, cryptophthalmos was observed in 85 to 93% of the patients (Gattuso et al., 1987; Slavotinek and Tifft, 2002; Thomas et al., 1986; van Haelst et al., 2007). Whereas the association of cryptophthalmos, syndactyly and urogenital malformations is highly specific of Fraser syndrome, cryptophthalmos is not mandatory in Fraser syndrome. In the literature, four cases of Fraser syndrome without cryptophthalmos have been described but no options for molecular confirmation were available at that time (Burn and Marwood, 1982; Koenig and Spranger, 1986; Lurie and Cherstvoy, 1984). Prenatal diagnosis of Fraser syndrome could be difficult. Tessier et al. analyzed the largest cohort of fetal cases of Fraser syndrome ever described (38 cases) and found that major diagnostic criteria, as syndactyly, cryptophthalmos or genital anomalies, are rarely found on prenatal ultrasonography, although they are easily identified on postnatal fetal examination (Tessier et al., 2016). The diagnosis should be considered by the association of CHAOS (Congenital High Airway Obstruction Sequence), oligohydramnios and renal agenesis. None of these features was present in Patient 1. In our patients, the diagnosis was confirmed by the detection of bi-allelic pathogenic FRAS1 mutations: either the association of a missense mutation in the first part of the gene and a nonsense mutation located in the last exons of the gene, or a homozygous frameshift mutation located in the
7
last exon of the gene, likely escaping nonsense mediated decay (NMD) of the mRNA, leading to the loss of the 35 most C-terminal amino acids.
So far, 28 variants have been reported in FRAS1 gene in the databases HGMD and ClinVar, most of them being truncating variants located between exon 5 and exon 71. The rarity of this syndrome and the difficulties of FRAS1 sequencing due its large number of exons hampered establishing phenotypegenotype correlations. The first publication of FRAS1 variants in Fraser syndrome reported four homozygous nonsense variants and one homozygous frameshift variant (resulting in termination of the protein three amino acids later), located between exons 29 and 61 and predicted to cause loss of function but with no correlation between the location of the variant and the phenotype (McGregor et al., 2003). Later publications of Fraser syndrome due to FRAS1 mutations were not comparable to our cases, because of the severity of the phenotype, the presence of cryptophthalmos, and the characteristics of the FRAS1 variants (frameshift variant associated with intragenic deletion (exons 3 to 14) of FRAS1, and compound heterozygous truncating variants in the first exons of FRAS1) (Hoefele et al., 2013; Slavotinek et al., 2006). Recently, Nayak et al. reported familial cases of Fraser syndrome due to homozygous splice site FRAS1 variant (junction intron 26 and exon 27), but the patients had severe and lethal phenotypes (Nayak et al., 2017). Biallelic missense FRAS1 variant were reported in 5 patients presenting with isolated congenital anomalies of the kidneys and urinary tract (CAKUT) (Kohl et al., 2014). One of them had an associated anal atresia. Only one patient harboring a FRAS1 truncating variant in exon 55 and a FRAS1 missense variant in exon 64 has been described in isolated CAKUT.
We describe for the first time novel variants in the FRAS1 gene in patients with Fraser syndrome without cryptophthalmos. These unusual presentations could be due to the characteristics of the FRAS1 variants, either the association of missense and truncating variants, or a homozygous
8
frameshift variant in the last exon of the gene. This hypothesis is supported by the previous observations of CAKUT in patients with biallelic missense FRAS1 variants, and by the fact that most of the previously described patients with typical Fraser syndrome do not harbor FRAS1 variants in the last exons. However, this hypothesis could be questioned by the following facts. First, 3 families with biallelic FRAS1 missense variants have been reported with a Fraser syndrome form with multiple malformations. For 2 families, the homozygous missense variants were located in 3’ exons of the gene (exon 63 and exon 65 respectively), outside of any known functional domains(van Haelst et al., 2008). The last patient carried compound heterozygous missense variants, one located in a furin-like domain, another in the last exons of the gene (exon 74), outside of any known functional domain (Ng et al., 2013). Furthermore, variants reported in CAKUT are localized from c.4159 to c.9959, out of the C-term region. The wide clinical heterogeneity of Fraser syndrome, illustrated with our atypical cases, remains difficult to explain. Description of larger cohorts of FRAS1 mutated patients and functional studies are required to better understand this variability of expression and the consequences of the observed missense mutations.
9
FIGURES/TABLES LEGENDS Table 1 – Phenotypes of our patients compared to the clinical presentation of the patients previously reported in the literature (frequency in %)
Main series of Fraser syndrome patients Our patients Clinical features
Van Haelst et al. (2007)
Slavotinek et al. (2002)
Gattuso et al. (1987)
Thomas et al. (1986)
59
117
68
124
Patient 1
Patient 2
Cryptophthalmos
-
-
85
88
93
85
Membranous syndactyly Genital malformations Urinary tract anomalies
+ + -
+ + +
95 66 80
62 40 49
54 30 37
79 60 80
- bilateral renal agenesis
-
-
36
23
-
58
- unilateral renal agenesis - uni- or bilateral renal hypoplasia - uni- or bilateral ureteral agenesis - bladder anomalies
-
+
41
22
-
33
-
-
15
-
-
10
-
-
10
-
-
-
-
-
17
17
10
-
Airway malformations - laryngeal anomalies
-
+ +
58 49
31
21
83
- tracheal anomalies
-
-
14
+ +
+ -
17 75 29 9 53
34 59 11 11 55
34 44 6 7 37
27 84 11 85
-
+ -
12 5 32 10 7
8 16 12 5
6 6 19
2 6 81
Number of patients
Dysmorphy - abnormal hair line - ear dysplasia - low-set umbilicus - cleft lip and/or palate - nasal anomalies Other malformations - skull ossification defects - meningo-encephalocele - anal atresia/stenosis - congenital heart defects Intellectual disability
10
Figure 1 - Patient 1 (A) Facial appearance at the age of 10 months, showing partial and symmetrical coloboma of both nostrils; (B,C) Small and dysplastic ears, with ear lobe hypoplasia. (D) Feet’s aspect at the age of 10 months, showing partial I-II and complete II-V bilateral membranous syndactyly; (E) Hands’ aspect at the age of 27 months, showing partial I-II membranous syndactyly of the right hand with a large space between the second and third rays; Patient 2 (F) Hands’ aspect in the neonatal period, with II-V bilateral syndactyly; (G) Hand’s aspect after surgery.
11
REFERENCES Barisic, I., Odak, L., Loane, M., Garne, E., Wellesley, D., Calzolari, E., Dolk, H., Addor, M.-C., Arriola, L., Bergman, J., Bianca, S., Boyd, P.A., Draper, E.S., Gatt, M., Haeusler, M., Khoshnood, B., LatosBielenska, A., McDonnell, B., Pierini, A., Rankin, J., Rissmann, A., Queisser-Luft, A., VerellenDumoulin, C., Stone, D., Tenconi, R., 2013. Fraser syndrome: epidemiological study in a European population. Am. J. Med. Genet. A. 161A, 1012–1018. https://doi.org/10.1002/ajmg.a.35839 Burn, J., Marwood, R.P., 1982. Fraser syndrome presenting as bilateral renal agenesis in three sibs. J. Med. Genet. 19, 360–361. Fraser, G.R., 1962. Our genetical ‘load’. A review of some aspects of genetical variation. Ann. Hum. Genet. 25, 387–415. https://doi.org/10.1111/j.1469-1809.1962.tb01774.x Gattuso, J., Patton, M.A., Baraitser, M., 1987. The clinical spectrum of the Fraser syndrome: report of three new cases and review. J. Med. Genet. 24, 549–555. Hoefele, J., Wilhelm, C., Schiesser, M., Mack, R., Heinrich, U., Weber, L.T., Biskup, S., Daumer-Haas, C., Klein, H.-G., Rost, I., 2013. Expanding the mutation spectrum for Fraser syndrome: identification of a novel heterozygous deletion in FRAS1. Gene 520, 194–197. https://doi.org/10.1016/j.gene.2013.02.031 Jadeja, S., Smyth, I., Pitera, J.E., Taylor, M.S., van Haelst, M., Bentley, E., McGregor, L., Hopkins, J., Chalepakis, G., Philip, N., Perez Aytes, A., Watt, F.M., Darling, S.M., Jackson, I., Woolf, A.S., Scambler, P.J., 2005. Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nat. Genet. 37, 520–525. https://doi.org/10.1038/ng1549 Koenig, R., Spranger, J., 1986. Cryptophthalmos--syndactyly syndrome without cryptophthalmos. Clin. Genet. 29, 413–416. Kohl, S., Hwang, D.-Y., Dworschak, G.C., Hilger, A.C., Saisawat, P., Vivante, A., Stajic, N., Bogdanovic, R., Reutter, H.M., Kehinde, E.O., Tasic, V., Hildebrandt, F., 2014. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J. Am. Soc. Nephrol. JASN 25, 1917–1922. https://doi.org/10.1681/ASN.2013101103 Lurie, I.W., Cherstvoy, E.D., 1984. Renal agenesis as a diagnostic feature of the cryptophthalmossyndactyly syndrome. Clin. Genet. 25, 528–532. McGregor, L., Makela, V., Darling, S.M., Vrontou, S., Chalepakis, G., Roberts, C., Smart, N., Rutland, P., Prescott, N., Hopkins, J., Bentley, E., Shaw, A., Roberts, E., Mueller, R., Jadeja, S., Philip, N., Nelson, J., Francannet, C., Perez-Aytes, A., Megarbane, A., Kerr, B., Wainwright, B., Woolf, A.S., Winter, R.M., Scambler, P.J., 2003. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat. Genet. 34, 203–208. https://doi.org/10.1038/ng1142 Nayak, S.S., Salian, S., Shukla, A., Mathew, M., Girisha, K.M., 2017. Variable presentation of Fraser syndrome in two fetuses and a novel mutation in FRAS1. Congenit. Anom. 57, 83–85. https://doi.org/10.1111/cga.12188 Ng, W.Y., Pasutto, F., Bardakjian, T.M., Wilson, M.J., Watson, G., Schneider, A., Mackey, D.A., Grigg, J.R., Zenker, M., Jamieson, R.V., 2013. A puzzle over several decades: eye anomalies with FRAS1 and STRA6 mutations in the same family. Clin. Genet. 83, 162–168. https://doi.org/10.1111/j.1399-0004.2012.01851.x Slavotinek, A., Li, C., Sherr, E.H., Chudley, A.E., 2006. Mutation analysis of the FRAS1 gene demonstrates new mutations in a propositus with Fraser syndrome. Am. J. Med. Genet. A. 140, 1909–1914. https://doi.org/10.1002/ajmg.a.31399 Slavotinek, A.M., Tifft, C.J., 2002. Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J. Med. Genet. 39, 623–633. Tessier, A., Sarreau, M., Pelluard, F., André, G., Blesson, S., Bucourt, M., Dechelotte, P., Faivre, L., Frébourg, T., Goldenberg, A., Goua, V., Jeanne-Pasquier, C., Guimiot, F., Laquerriere, A.,
12
Laurent, N., Lefebvre, M., Loget, P., Maréchaud, M., Mechler, C., Perez, M.-J., Sabourin, J.C., Verloes, A., Patrier, S., Guerrot, A.-M., 2016. Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases. Prenat. Diagn. 36, 1270–1275. https://doi.org/10.1002/pd.4971 Thomas, I.T., Frias, J.L., Felix, V., Sanchez de Leon, L., Hernandez, R.A., Jones, M.C., 1986. Isolated and syndromic cryptophthalmos. Am. J. Med. Genet. 25, 85–98. https://doi.org/10.1002/ajmg.1320250111 van Haelst, M.M., Maiburg, M., Baujat, G., Jadeja, S., Monti, E., Bland, E., Pearce, K., Fraser Syndrome Collaboration Group, Hennekam, R.C., Scambler, P.J., 2008. Molecular study of 33 families with Fraser syndrome new data and mutation review. Am. J. Med. Genet. A. 146A, 2252– 2257. https://doi.org/10.1002/ajmg.a.32440 van Haelst, M.M., Scambler, P.J., Fraser Syndrome Collaboration Group, Hennekam, R.C.M., 2007. Fraser syndrome: a clinical study of 59 cases and evaluation of diagnostic criteria. Am. J. Med. Genet. A. 143A, 3194–3203. https://doi.org/10.1002/ajmg.a.31951 Vogel, M.J., van Zon, P., Brueton, L., Gijzen, M., van Tuil, M.C., Cox, P., Schanze, D., Kariminejad, A., Ghaderi-Sohi, S., Blair, E., Zenker, M., Scambler, P.J., Ploos van Amstel, H.K., van Haelst, M.M., 2012. Mutations in GRIP1 cause Fraser syndrome. J. Med. Genet. 49, 303–306. https://doi.org/10.1136/jmedgenet-2011-100590
13