Chromosome 5q12 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome on chromosome 5q12.

Clinical Features

Jaillard et al. (2011) reported 4 unrelated children with developmental delay or mental retardation and facial dysmorphism who were found to have small heterozygous de novo deletions of chromosome 15q12. The deletions were detected by array comparative genomic hybridization (array CGH). Three patients had growth retardation. One patient had neonatal hypotonia and seizures. Three patients had visual impairment, 2 of whom had hypermetropia. Dysmorphic features included coarse facies, large forehead, frontal bossing, large nose and nasal tip, and esotropia. More variable features included long or short philtrum, hyper- or hypotelorism, ptosis, thin palpebral fissures, and thin upper lip. Skeletal abnormalities were also variable, including brachymesophalangy, short arms, flat feet, joint laxity, and brachycephaly. One patient with short long bones also carried a mutation in the FGFR3 gene (N540S; 134934.0023), consistent with hypochondroplasia (146000). Lindstrand et al. (2014) concluded that the facial phenotype of patient 1 reported by Jaillard et al. (2011) was reminiscent of acrodysostosis-2 (ACRDYS2; 614613; see CYTOGENETICS).

Lindstrand et al. (2014) reported 3 unrelated girls with de novo heterozygous copy number variations of 5q12. The patients had mild intellectual disability, low body mass index, long limbs, fingers, and toes, and low blood pressure. Dysmorphic facial features included prominent nose, posteriorly rotated ears, long palpebral fissures, and micrognathia. One patient had autistic features.

Cytogenetics

The deletions at 5q12 in the 4 patients reported by Jaillard et al. (2011) ranged from 5.75 to 17.26 Mb, with a common 2.63-Mb deleted region on chromosome 5q12.1, including 12 genes.

Lindstrand et al. (2014) reported 2 unrelated girls with heterozygous de novo deletions of 5q11.2-q12.1 ascertained from a cohort of 3,117 patients referred for array CGH analysis due to a suspected genomic imbalance. The deletions were 10.2 and 8.4 Mb, respectively, and both included the entire PDE4D gene (600129), resulting in haploinsufficiency for that gene. A third unrelated girl with a similar phenotype was found to carry a de novo heterozygous 784-kb intragenic duplication of exons 2 to 6 of the PDE4D gene, which resulted in a loss of gene function and haploinsufficiency like that of the first 2 girls.

Lindstrand et al. (2014) noted that heterozygous gain-of-function mutations in the PDE4D gene lead to a 'mirror' phenotype, acrodysostosis-2, which is characterized by nasal and maxillary hypoplasia, short extremities, and brachydactyly, in addition to intellectual disability. Lindstrand et al. (2014) noted that 1 of the breakpoints in patient 1 reported by Jaillard et al. (2011) was within the PDE4D gene, and that only the exons coding for the UCR1 inhibitory domain were affected. The predicted cellular consequence of this deletion would thus be increased activity of the enzyme and lower cAMP levels, as observed in patients with ACRDYS2. Lindstrand et al. (2014) stated that the facial features of this patient were more similar to those of acrodysostosis with maxillary hypoplasia and a short nose, although these features had not been noted by Jaillard et al. (2011).