2012
DOI: 10.1016/j.ajhg.2012.04.004
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Haploinsufficiency of SF3B4, a Component of the Pre-mRNA Spliceosomal Complex, Causes Nager Syndrome

Abstract: Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal com… Show more

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Cited by 187 publications
(218 citation statements)
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“…It is well known that PUF60 encodes a splicing factor that interacts directly with SF3B4, a component of the U2 pre-mRNA spliceosomal complex involved in Nager syndrome, suggesting that PUF60 and SF3B4 haploinsufficiency-associated phenotypes are partially due to a defect of spliceosome function. 8,14 Interestingly, the patient carrying a PUF60 variant reported by Dauber et al 8 (patient 6) harbors clinical signs belonging to the Nager syndrome spectrum, including hemifacial microsomia with micro-retrognathism and preaxial upper-limb anomalies with an absent right thumb and hypoplastic metacarpal and scaphoid bones (Table 1). 8 In conclusion, these results highlight the power of WES as an unbiased NGS-based strategy for identifying new genes causing very rare multisystemic conditions, 15 and the importance of data sharing to identify their underlying clinical expression that is otherwise hampered by the paucity of reported cases.…”
Section: Discussionmentioning
confidence: 99%
“…It is well known that PUF60 encodes a splicing factor that interacts directly with SF3B4, a component of the U2 pre-mRNA spliceosomal complex involved in Nager syndrome, suggesting that PUF60 and SF3B4 haploinsufficiency-associated phenotypes are partially due to a defect of spliceosome function. 8,14 Interestingly, the patient carrying a PUF60 variant reported by Dauber et al 8 (patient 6) harbors clinical signs belonging to the Nager syndrome spectrum, including hemifacial microsomia with micro-retrognathism and preaxial upper-limb anomalies with an absent right thumb and hypoplastic metacarpal and scaphoid bones (Table 1). 8 In conclusion, these results highlight the power of WES as an unbiased NGS-based strategy for identifying new genes causing very rare multisystemic conditions, 15 and the importance of data sharing to identify their underlying clinical expression that is otherwise hampered by the paucity of reported cases.…”
Section: Discussionmentioning
confidence: 99%
“…Genome-wide association studies have been pivotal to the identification of a number of loci and genetic variants associated to craniofacial anomalies (Grant et al 2009;Beaty et al 2010;Mangold et al 2010;Dixon et al 2011) and also suggest genes linked to normal variation in facial structure (Liu et al 2012). Similarly, recent studies using exome sequencing have been used to map the causes of craniofacial defects in conditions such as Miller syndrome (Ng et al 2010) and Nager syndrome (Bernier et al 2012). Current transcriptome and epigenomic analysis should accelerate the dissection of the genetic basis of neural crest-related syndromes through regulatory network comparisons between normal and disease states.…”
Section: Neural Crest Cells and Diseasementioning
confidence: 99%
“…Researchers asserted the utility of exome sequencing in "the diagnostic algorithm for infants presenting with congenital dislocations, chondrodysplasia, and short stature" [39]. Exome sequencing may prove equally valuable in early screening for heritable, but poorly understood, conditions such as metachondromatosis [40], Hajdu-Cheney [41], Early Onset Generalized Dystonia [42], Distal Arthrogryposis Type 1 [43], and Nager syndrome [44].…”
Section: Musculoskeletalmentioning
confidence: 99%