Deletion of a 760 kb region at 4p16 determines the prenatal and postnatal growth retardation characteristic of Wolf-Hirschhorn syndrome

• Published in: Journal of medical genetics Vol. 44; no. 10; pp. 647 - 650
• Main Authors: Concolino, Daniela, Rossi, Elena, Strisciuglio, Pietro, Iembo, Maria Antonietta, Giorda, Roberto, Ciccone, Roberto, Tenconi, Romano, Zuffardi, Orsetta
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-10-2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Age; Artificial chromosomes; Biological and medical sciences; CGH; Child, Preschool; Chromosomes, Human, Pair 4; Classical genetics, quantitative genetics, hybrids; comparative genomic hybridisations; Complex syndromes; Cytogenetics; Deoxyribonucleic acid; Developmental Disabilities - genetics; DNA; Facies; Female; FISH; fluorescence in situ hybridisation; Fundamental and applied biological sciences. Psychology; Gene Deletion; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genotype; Growth hormones; Human; Humans; In Situ Hybridization, Fluorescence; Kidneys; Letter to JMG; Manufacturers; Medical genetics; Medical sciences; Microcephaly - genetics; Models, Genetic; Molecular and cellular biology; Mutation; Nucleic Acid Hybridization; Patients; Phenotype; Syndrome; Ultrasonic imaging; WHS; Wolf-Hirschhorn syndrome; Chromosomal aberration; Genetic mapping; Human; Prenatal; Wolf Hirschhorn syndrome; Malformation; Deletion; Genetics; Complex syndrome; Postnatal development; Growth retardation
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2007.050963

Background: Recently the genotype/phenotype map of Wolf-Hirschhorn syndrome (WHS) has been refined, using small 4p deletions covering or flanking the critical region in patients showing only some of the WHS malformations. Accordingly, prenatal-onset growth retardation and failure to thrive have been found to result from haploinsufficiency for a 4p gene located between 0.4 and 1.3 Mb, whereas microcephaly results from haploinsufficiency of at least two different 4p regions, one of 2.2–2.38 Mb and a second one of 1.9–1.28 Mb. Methods and Results: We defined the deletion size of a ring chromosome (r(4)) in a girl with prenatal onset growth retardation, severe failure to thrive and true microcephaly but without the WHS facial gestalt and mental retardation. A high-resolution comparative genome hybridisation array revealed a 760 kb 4p terminal deletion. Conclusions: This case, together with a familial 4p deletion involving the distal 400 kb reported in normal women, may narrow the critical region for short stature on 4p to 360–760 kb. This region is also likely to contain a gene for microcephaly. “In silico” analysis of all genes within the critical region failed to reveal any strikingly suggestive expression pattern; all genes remain candidates for short stature and microcephaly.