BMP4 gene


Gene (OMIM No.)
Function of gene/protein
  • Protein: bone morphogenetic protein 4
  • Crucial for lens induction and invagination of the optic vesicle during eye organogenesis
  • Induces formation of bones, connective tissues, skeletal muscle and the urogenital system (derived from mesoderm)
Clinical phenotype
(OMIM phenotype no.)
  • Autosomal dominant
Ocular features
Systemic features
  • Brain anomalies (cortical atrophy, small cerebellum, corpus callosum hypoplasia, cortical atrophy)
  • Neurological (hypotonia, seizures, psychomotor retardation)
  • Craniofacial (brachycephaly, macrocephaly, high forehead, facial asymmetry, retrognathia, micrognathia, midface hypoplasia, cleft and high-arched palate, bifid uvula, large, flat and posteriorly rotated ears)
  • Endocrine (pituitary hypoplasia, hypopituitarism)
  • Genitourinary (micropenis, hypospadias, cryptorchidism, absent uterine horn, underdeveloped genitalia, hypolastic kidneys, hypoplastic adrenal glands)
  • Skeletal (cervical vertebral anomalies, short middle phalanges, pre- and post-axial polydactyly, syndactyly, brachydactyly)
Key investigations
  • B-scan USS to measure axial length to document microphthalmia
  • Electrophysiology
  • MRI brain and orbit
  • Systemic assessment with a paediatrician and other relevant specialists
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (MAC)
  • Whole genome sequencing
  • Multidisciplinary approach
Therapies under research
  • None at present
Further information

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Additional information

The BMP4 gene is located adjacent to the OTX2 gene in the chromosome 14q locus. Contiguous gene deletion of both BMP4 and OTX2 (14q22 microdeletion syndrome) can give rise to phenotypes overlapping both genes, which include MAC, anterior segment dysgenesis, midline structural abnormalities (pituitary and corpus callosum) and white matter loss.

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  1.  Bakrania P, Efthymiou M, Klein JC, et al. Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet. 2008;82(2):304‐319
  2.  Bennett CP, Betts DR, Seller MJ. Deletion 14q (q22q23) associated with anophthalmia, absent pituitary, and other abnormalities. J Med Genet. 1991;28(4):280‐281
  3.  Castilla EE, Martínez-Frías ML. Congenital healed cleft lip. Am J Med Genet. 1995;58(2):106‐112
  4.  Elliott J, Maltby EL, Reynolds B. A case of deletion 14(q22.1–>q22.3) associated with anophthalmia and pituitary abnormalities. J Med Genet. 1993;30(3):251‐252
  5.  Phadke SR, Sharma AK, Agarwal SS. Anophthalmia with cleft palate and micrognathia: a new syndrome?. J Med Genet. 1994;31(12):960‐961
  6.  Brisset S, Slamova Z, Dusatkova P, et al. Anophthalmia, hearing loss, abnormal pituitary development and response to growth hormone therapy in three children with microdeletions of 14q22q23. Mol Cytogenet. 2014;7(1):17
  7.  Nolen LD, Amor D, Haywood A, et al. Deletion at 14q22-23 indicates a contiguous gene syndrome comprising anophthalmia, pituitary hypoplasia, and ear anomalies
  8.  Takenouchi T, Nishina S, Kosaki R, et al. Concurrent deletion of BMP4 and OTX2 genes, two master genes in ophthalmogenesis. Eur J Med Genet. 2013;56(1):50‐53

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Updated on November 30, 2020

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