Elsevier

Gene

Volume 520, Issue 2, 15 May 2013, Pages 194-197
Gene

Short Communication
Expanding the mutation spectrum for Fraser syndrome: Identification of a novel heterozygous deletion in FRAS1

https://doi.org/10.1016/j.gene.2013.02.031Get rights and content

Highlights

  • A large deletion of FRAS1 should be considered in patients with one FRAS1 mutation.

  • Array-CGH represents an important and valuable addition in the diagnostics of FS.

  • Patients with deletions have a similar phenotype as with known types of mutations.

Abstract

Fraser syndrome (FS) is a rare autosomal recessive inherited disorder characterized by cryptophthalmos, laryngeal defects and oral clefting, mental retardation, syndactyly, and urogenital defects. To date, 250 patients have been described in the literature. Mutations in the FRAS1 gene on chromosome 4 have been identified in patients with Fraser syndrome. So far, 26 mutations have been identified, most of them are truncating mutations. The mutational spectrum includes nucleotide substitutions, splicing defects, a large insertion, and small deletions/insertions. Moreover, single heterozygous missense mutations in FRAS1 seem to be responsible for non-syndromic unilateral renal agenesis.

Here we report the first case of a family with two patients affected by Fraser syndrome due to a deletion of 64 kb (deletion 4q21.21) and an additional novel frameshift mutation in exon 66 of the FRAS1 gene. To date, large deletions of the FRAS1 gene have not yet been described. Large deletions seem to be a rare cause for Fraser syndrome, but should be considered in patients with a single heterozygous mutation.

Introduction

Fraser syndrome (FS; OMIM #219000) is a rare autosomal recessive disorder characterized by cryptophthalmos, syndactyly, abnormalities of the respiratory and urogenital tract (Fraser, 1962, Slavotinek and Tifft, 2002, van Haelst et al., 2007). Thomas et al. implemented diagnostic criteria for FS dividing into major criteria (cryptophthalmos; syndactyly; abnormal genitalia; an affected sibling) and minor criteria (congenital malformation of the nose, ears and larynx; cleft lip/palate; skeletal malformations; renal agenesis; mental retardation; umbilical hernia) (Thomas et al., 1986, van Haelst et al., 2007). FS can be diagnosed, if two major and one minor criteria or one major and four minor criteria are present (van Haelst et al., 2007). FS shows an interfamilial highly variable phenotype ranging from minor symptoms to lethal malformations like renal agenesis. On the other hand, a strong phenotypic similarity exists within a family (Slavotinek and Tifft, 2002). The incidence of FS has been found to be 0.43 per 100,000 live births (Martinez-Frias et al., 1994). Mutations in the FRAS1, FREM2, and GRIP1 gene have been identified causing FS (McGregor et al., 2003, Vogel et al., 2012). Mutations in FRAS1 are responsible for the classical phenotype of FS (McGregor et al., 2003). FREM1 mutations can also be associated with a less severe phenotype as seen in Manitoba Oculotrichoanal Syndrome (MOTA; OMIM #248450) and bifid nose, with or without anorectal and renal anomalies (BNAR; OMIM #608980) (Vogel et al., 2012). Mutations in FREM2 can also be found in a subset of FS patients suggesting heterogeneity of this syndrome (Smyth and Scambler, 2005). Almost 50% of the patients exhibit mutations in either of the genes. The molecular defect underlying the other half still remains unknown. The FRAS1 gene is located on chromosome 4q21.21 and encodes a protein that is widely expressed. It has sequence similarity to genes encoding for a set of extracellular matrix (ECM) proteins (McGregor et al., 2003). Up to now, nucleotide substitutions, splicing defects, a large insertion, and small deletions/insertions have been described to be responsible for FS. 26 mutations are listed in HGMD (http://www.biobase-international.com), most of them are truncating.

Here we report the first case of a family with two fetuses affected by FS carrying – besides a novel frameshift mutation – a deletion of several exons of the FRAS1 gene. To our knowledge, large deletions in FRAS1 have not yet been described. Deletions of the FRAS1 gene therefore seem to be a rare cause for FS.

Section snippets

Case report

The family is of German origin and presented to our department in 2012 for genetic counseling (pedigree is shown in Fig. 1). The medical history revealed a tubal pregnancy in 1995. During the second pregnancy in 2005 prenatal ultrasound showed a female fetus with renal agenesis on the left side and a multicystic dysplastic kidney on the right side. The thorax seemed hypoplastic and there was anhydramnia. The fetus was stillborn at 29 weeks of gestation (Fig. 1). Post mortem investigations

Results

Mutational analysis of the first fetus could not be performed for all exons of the FRAS1 gene because of poor DNA quality. Therefore, mutational analysis was first done in the parents. In exon 66 of the FRAS1 gene the novel heterozygous mutation c.10346delA resulting in a premature stop (p.Glu3449GlyfsX2) was identified in the father (Fig. 3). Targeted diagnostic sequencing revealed that the first fetus was carrier of the paternal mutation. Examination of the second fetus, which was performed

Discussion

Fraser syndrome is characterized by cryptophthalmus, syndactyly, and urogenital defects (Slavotinek et al., 2006). So far, all known FRAS1 mutations are missense or nonsense mutations, splicing defect, small deletions and insertions. FRAS1 mutations can be identified in 40–50% of the patients. Slavotinek first described a patient with a single mutation in the FRAS1 gene (Slavotinek et al., 2006). A further molecular study of 33 families with FS identified two non-consanguineous families with a

Acknowledgments

We would like to thank the family for participation.

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