14. Prenatal diagnosis of Acrofacial Dysostosis type 1 (Nager syndrome) by chromosomal microarray at the exon level

      Nager syndrome or Acrofacial Dysostosis type 1 (OMIM #154400) is a rare, autosomal dominant syndrome characterized by craniofacial malformations. Fewer than 100 cases have been reported in the literature and of these, only 11 were suspected prenatally. Major phenotypic findings include micrognathia, ear anomalies and limb malformations; however, the severity is variable. Haploinsufficiency of the SF3B4 (1q21.2) gene is the most commonly recognized etiology of Nager syndrome and can be identified in more than 50% of clinically affected patients. SF3B4 encodes for the SAP49 protein which is a component of the spliceosome and has a role in the bone morphogenic protein pathway. The majority of Nager syndrome cases involve missense and nonsense mutations, or whole gene deletions. We report on a 20 year old primigravida who underwent amniocentesis at 23+1 weeks due to ultrasound findings of severe micrognathia, ear anomalies, mild hypotelorism, and absent left thumb. Chromosome microarray identified a 166kb partial deletion of the SF3B4 gene spanning exons 3-6. Copy number PCR was performed to confirm the finding and to determine whether the deletion was maternally inherited. Both independent DNA extractions of the amniotic fluid sample had a copy number of one and the maternal sample had a copy number of two, confirming the deletion. To the best of our knowledge, this prenatal diagnosis of Nager syndrome by chromosomal microarray is the first partial gene deletion of SF3B4 reported. Further, this demonstrates the importance of chromosomal microarray in correlating fetal ultrasound findings with genetic etiology. Knowledge of this result prior to birth allowed more robust family counseling about the findings and prognosis, along with adequate medical preparation for the anticipated complex interventional needs of the neonate at and after delivery.
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