Unique phenotype in a patient with CHARGE syndrome

Abstract

CHARGE is a phenotypically heterogeneous autosomal dominant disorder recognized as a cohesive syndrome since the identification of CHD7 as a genetic etiology. Classic features include: Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genitourinary abnormalities, and Ear anomalies and/or deafness. With greater accessibility to genetic analysis, a wider spectrum of features are emerging, and overlap with disorders such as DiGeorge syndrome, Kallmann syndrome, and Hypoparathyroidism Sensorineural Deafness and Renal Disease syndrome, is increasingly evident. We present a patient with a unique manifestation of CHARGE syndrome, including primary hypoparathyroidism and a limb anomaly; to our knowledge, he is also the first CHARGE subject reported with bilateral multicystic dysplastic kidneys. Furthermore, with structural modeling and murine expression studies, we characterize a putative CHD7 G744S missense mutation. Our report continues to expand the CHARGE phenotype and highlights that stringent fulfillment of conventional criteria should not strictly guide genetic analysis.

Figure 1

A patient with a unique presentation of CHARGE syndrome and a G744S CHD7 mutation. A. Pedigree of a CHARGE patient with a novel CHD7 mutation. circle: female; square: male; arrow: proband; +: wild type allele. B. Photographs of the facies (I), eyes (II), and hands (III) of the CHD7 G744S heterozygous proband. C. Evolutionary conservation of the residue Gly744. ClustalW multiple alignment of partial protein sequence of CHD7 orthologs. The position of residue G744 altered by one heterozygous nucleotide change is marked by arrow and red letters in the corresponding segment of the multiple alignment. The amino acid residues that differ from the sequence of the human CHD7 protein are indicated blue. Gly744 residue is evolutionarily fully conserved in all fifteen available CHD7 orthologs. D. Structural model of the amino acid regions spanning 651-794 of the CHD7 protein obtained by sequence homology to a bacterial flagellar filament. The site of the mutation (indicated in magenta), which is predicted to be detrimental by POLYPHEN, lies on a protein interaction surface as indicated by SSPIDER.

Figure 2

Chd7 expression in the developing mouse. At E11.5 Chd7 is broadly expressed and shows prominent signals with the Chd7 antisense probe in DIG labeled whole mount in-situ hybridization in the region of the distal tip of the limb buds (see also enlargements on the right). T: telencephalic vesicle, E: corneal ectoderm overlying lens vesicle, M: maxillary component of first branchial arch, H: heart, FL: forelimb, HL: hindlimb.