title: Familial co-segregation of Coffin-Lowry syndrome inherited from the mother and autosomal dominant Waardenburg type IV syndrome due to deletion of EDNRB inherited from the father.
abstract: We report an African-American family that was identified after the proposita was referred for diagnostic evaluation at 4½ months with a history of Hirschsprung and dysmorphic features typical of Waardenburg syndrome (WS). Family evaluation revealed that the father had heterochromidia irides and hypertelorism supporting the clinical diagnosis of WS; however, examination of the mother revealed characteristic facial and digital features of Coffin-Lowry syndrome (CLS). Molecular testing of the mother identified a novel 2 bp deletion (c.865_866delCA) in codon 289 of RPS6KA3 leading to a frame-shift and premature termination of translation 5 codons downstream (NM_004586.2:p.Gln289ValfsX5). This deletion also was identified in the proposita and her three sisters with a clinical suspicion of CLS, all of whom as carriers for this X-linked disorder had very subtle manifestations. The molecular confirmation of WS type 4 (Shah-Waardenburg; WS4) was not as straightforward. To evaluate WS types 1-4, multiple sequential molecular tests were requested, including Sanger sequencing of all exons, and deletion/duplication analysis using MLPA for PAX3, MITF, SOX10, EDN3 and EDNRB. Although sequencing did not identify any disease causing variants, MLPA identified a heterozygous deletion of the entire EDNRB in the father. This deletion was also found in the proposita and the oldest child. Since the heterozygous deletion was the only change identified in EDNRB, this family represents one of the few cases of an autosomal dominant inheritance of WS4 involving the endothelin pathway. Altogether, clinical evaluation of the family revealed one child to be positive for WS4 and two positive for CLS, while two children were positive for both diseases simultaneously (including the proposita) while another pair test negative for either disease. This kinship is an example of the coincidence of two conditions co-segregating in one family, with variable phenotypes requiring molecular testing to confirm the clinical diagnoses.
authors.affiliation: Department of Genetics, LSU Health Sciences Center, New Orleans, LA, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Loupe
authors.affiliation: Department of Genetics, LSU Health Sciences Center, New Orleans, LA, USA.
authors.forename: Srirangan
authors.initials: S
authors.lastname: Sampath
authors.affiliation: Department of Pediatrics, Division of Genetics, LSU Health Sciences Center and Children's Hospital, New Orleans, LA, USA. Electronic address: ylacassi@chnola.org.
authors.forename: Yves
authors.initials: Y
authors.lastname: Lacassie
mesh_terms: D000328:Adult; D001741:Black or African American; D001483:Base Sequence; D002648:Child; D002872:Chromosome Deletion; D020090:Chromosome Segregation; D041321:Chromosomes, Human, X; D003062:Codon; D038921:Coffin-Lowry Syndrome / Q000235:genetics*; D015897:Comorbidity; D004247:DNA; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005799:Genes, Dominant; D040941:Heredity; D006627:Hirschsprung Disease; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009679:Nuclear Family; D010375:Pedigree; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics*; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: D003062:Codon; C000588596:EDNRB protein, human; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D004247:DNA
keywords: Autosomal dominant inherited EDNRB deletion; Co-segregation; Coffin–Lowry syndrome; Waardenburg type IV