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Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome
  1. Paul Kruszka1,
  2. Dong Li2,
  3. Margaret H Harr3,
  4. Nathan R Wilson4,
  5. Daniel Swarr3,
  6. Elizabeth M McCormick3,
  7. Rosetta M Chiavacci2,
  8. Mindy Li3,
  9. Ariel F Martinez1,
  10. Rachel A Hart1,
  11. Donna M McDonald-McGinn3,
  12. Matthew A Deardorff3,
  13. Marni J Falk3,
  14. Judith E Allanson5,
  15. Cindy Hudson6,
  16. John P Johnson6,7,
  17. Irfan Saadi4,
  18. Hakon Hakonarson2,
  19. Maximilian Muenke1,
  20. Elaine H Zackai3
  1. 1Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  2. 2The Center for Applied Genomics, The Children's Hospital of Philadelphia, and the Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3Division of Human Genetics, The Children's Hospital of Philadelphia, Clinical Genetics Center, and the Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  4. 4Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
  5. 5Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
  6. 6Shodair Children's Hospital, Helena, Montana, USA
  7. 7Clinical Genetics and Metabolism, Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts, USA
  1. Correspondence to Dr Elaine H Zackai, Clinical Genetics Center, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA; zackai{at}


Background Opitz G/BBB syndrome is a heterogeneous disorder characterised by variable expression of midline defects including cleft lip and palate, hypertelorism, laryngealtracheoesophageal anomalies, congenital heart defects, and hypospadias. The X-linked form of the condition has been associated with mutations in the MID1 gene on Xp22. The autosomal dominant form has been linked to chromosome 22q11.2, although the causative gene has yet to be elucidated.

Methods and results In this study, we performed whole exome sequencing on DNA samples from a three-generation family with characteristics of Opitz G/BBB syndrome with negative MID1 sequencing. We identified a heterozygous missense mutation c.1189A>C (p.Thr397Pro) in SPECC1L, located at chromosome 22q11.23. Mutation screening of an additional 19 patients with features of autosomal dominant Opitz G/BBB syndrome identified a c.3247G>A (p.Gly1083Ser) mutation segregating with the phenotype in another three-generation family.

Conclusions Previously, SPECC1L was shown to be required for proper facial morphogenesis with disruptions identified in two patients with oblique facial clefts. Collectively, these data demonstrate that SPECC1L mutations can cause syndromic forms of facial clefting including some cases of autosomal dominant Opitz G/BBB syndrome and support the original linkage to chromosome 22q11.2.

  • Developmental
  • Diagnosis
  • Genetics
  • Clinical genetics

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