Variable expressivity of syndromic BMP4-related eye, brain, and digital anomalies: A review of the literature and description of three new cases.

Abstract

Microphthalmia with brain and digital anomalies (MCOPS6, MIM# 607932) is an autosomal dominant disorder caused by loss-of-function variants or large deletions involving BMP4, which encodes bone morphogenetic protein 4, a member of the TGF-β protein superfamily. BMP4 has a number of roles in embryonic development including neurogenesis, lens induction, development of cartilage and bone, urogenital development, limb and digit patterning, hair follicle regeneration, as well as tooth formation. In addition to syndromic microphthalmia, BMP4 variants have been implicated in non-syndromic cleft lip with or without cleft palate and congenital healed cleft lip indicating different allelic presentations. MCOPS6 subjects may also lack some of the major phenotypic hallmarks of the disorder, including microphthalmia, indicating variable expressivity. As only a handful of individuals with MCOPS6 have been described, we review the clinical findings in previously reported cases with either deletions or loss-of-function variants in BMP4. We describe three new cases, including two subjects with novel deletions and one subject with a likely pathogenic de novo nonsense variant [c.1052C>G, p.(S351*)] in BMP4. One of the subjects had dual molecular diagnoses including a co-occurring microdeletion at 17q21.31 associated with Koolen de Vries syndrome, which has a partially overlapping disease phenotype. None of these individuals had clinically apparent microphthalmia or anopthalmia, which have been reported in a majority of previously described cases. One subject had exophthalmia and strabismus, while another had bilateral Peters anomaly and sclerocornea, thus expanding the phenotype associated with BMP4 loss-of-function variants.

• Authors: Patrick R Blackburn, Cinthya J Zepeda-Mendoza, Teresa M Kruisselbrink, Lisa A Schimmenti, Sixto García-Miñaur, María Palomares, Julián Nevado, María A Mori, Guylène Le Meur, Eric W Klee, Cédric Le Caignec, Pablo Lapunzina, Bertrand Isidor, Dusica Babovic-Vuksanovic
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 27 Issue 9 Pg. 1379-1388 (09 2019) ISSN: 1476-5438 [Electronic] England
• PMID: 31053785 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• BMP4 protein, human
• Bone Morphogenetic Protein 4

Topics

• Abnormalities, Multiple (diagnosis, genetics)
• Adolescent
• Bone Morphogenetic Protein 4 (genetics)
• Child
• Child, Preschool
• Comparative Genomic Hybridization
• Eye Abnormalities (diagnosis, genetics)
• Facies
• Female
• Gene Expression Regulation
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genetic Variation
• Humans
• Infant
• Limb Deformities, Congenital (diagnosis, genetics)
• Magnetic Resonance Imaging
• Male
• Microcephaly (diagnosis, genetics)
• Pedigree
• Phenotype
• Radiography