Co‐occurrence of distinct ciliopathy diseases in single families suggests genetic modifiers

• Published in: American journal of medical genetics. Part A 2011-12, Vol.155 (12), p.3042-3049
• Main Authors: Zaki, Maha S., Sattar, Shifteh, Massoudi, Rustin A., Gleeson, Joseph G.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult and adolescent clinical studies; Bardet-Biedl syndrome; Bardet-Biedl Syndrome - complications; Bardet-Biedl Syndrome - diagnosis; Bardet-Biedl Syndrome - genetics; Biological and medical sciences; Brain - pathology; Cerebellar Diseases - complications; Cerebellar Diseases - diagnosis; Cerebellar Diseases - genetics; Child; Child, Preschool; Children; Clinical Reports; Consanguinity; Discordance; Diseases of the osteoarticular system; Facies; Female; Humans; Intellectual deficiency; intellectual disability; Kidney Diseases - complications; Kidney Diseases - diagnosis; Kidney Diseases - genetics; Kidney Diseases, Cystic - complications; Kidney Diseases, Cystic - congenital; Kidney Diseases, Cystic - diagnosis; Kidney Diseases, Cystic - genetics; Magnetic Resonance Imaging; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical genetics; Medical sciences; Mental retardation; Molars; molar‐tooth; Muscle Hypotonia - complications; Muscle Hypotonia - diagnosis; Muscle Hypotonia - genetics; Mutation; Nephronophthisis; Obesity; Ocular Motility Disorders - complications; Ocular Motility Disorders - diagnosis; Ocular Motility Disorders - genetics; Ophthalmology; Pedigree; Phenotype; Polydactyly; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; retinal blindness; Siblings; Teeth; Vision disorders
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.34173

Disorders within the “ciliopathy” spectrum include Joubert (JS), Bardet–Biedl syndromes (BBS), and nephronophthisis (NPHP). Although mutations in single ciliopathy genes can lead to these different syndromes between families, there have been no reports of phenotypic discordance within a single family. We report on two consanguineous families with discordant ciliopathies in sibling. In Ciliopathy‐672, the older child displayed dialysis‐dependent NPHP whereas the younger displayed the pathognomonic molar tooth MRI sign (MTS) of JS. A second branch displayed two additional children with NPHP. In Ciliopathy‐1491, the oldest child displayed classical features of BBS whereas the two younger children displayed the MTS. Importantly, the children with BBS and NPHP lacked MTS, whereas children with JS lacked obesity or NPHP, and the child with BBS lacked MTS and NPHP. Features common to all three disorders included intellectual disability, postaxial polydactyly, and visual reduction. The variable phenotypic expressivity in this family suggests that genetic modifiers may determine specific clinical features within the ciliopathy spectrum. © 2011 Wiley Periodicals, Inc.