Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome

Abstract

Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.

Nager Syndrome Does Not Preclude Organ Donation

“…Other mandibulofacial dysostoses such as type Toriello, type HederaToriello-Petty, type Bauru and type Verloes share similarities with NS in terms of facial and thumb anomalies [6].…”

A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome

“…6 The coding sequences of other 24 genes associated with mandibulo-facial and/or ear malformations were isolated and captured using the HaloPlex Target Enrichment system (Agilent Technologies, Santa Clara, CA, USA; Supplementary Table S1); indexed DNA fragments libraries were generated according to the manufacturer's protocol (version D.5) and sequenced on a MiSeq Dx instrument (Illumina, San Diego, CA, USA), with 150 bp paired-end sequencing. Variant calling and bioinformatic analyses for NGS experiments were performed using the SureCall software version v3.0.2.1 (Agilent Technologies).…”

“…[1][2][3] Haploinsufficiency of SF3B4, a gene encoding for a protein involved in the assembly of spliceosomal complexes, is the only known cause of Nager syndrome, that affects greater than 50% of clinically diagnosed patients. 4,5 Since 2012, heterozygous loss-of-function SF3B4 variants have been reported in 38 out of 62 pedigrees with a clinical diagnosis of this syndrome, suggesting genetic heterogeneity; [4][5][6][7][8][9] in addition, deletions encompassing SF3B4 have been detected in cases with clinical features of Nager syndrome. 9,10 In this article, we describe a three-generation family with Nager syndrome due to a SF3B4 synonymous variant leading to abnormal splicing of the primary transcript, as assessed through a hybrid minigene assay.…”

A 22-Week-Old Fetus with Nager Syndrome and Congenital Diaphragmatic Hernia due to a Novel <b><i>SF3B4</i></b> Mutation

“…Bernier et al [2012] identified 18 different heterozygous mutations in the SF3B4 gene in 20 families from a total of 35 pedigrees with a clinical diagnosis of AFD1. Sixteen additional families with molecularly confirmed AFD1 were subsequently reported [Czeschik et al, 2013;Petit et al, 2013]. In all but 4 cases, the diagnosis was established after birth.…”