Genotype–phenotype analysis of 4q deletion syndrome: Proposal of a critical region

Abstract

Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a ∼465 kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes.

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

“…The interstitial 4q28.2-31.2 deletion found in patient 3 overlapped with the 4q deletion syndrome, a rare (28). Pre-or postnatal-onset short stature has been reported in w50% of the cases, but the critical region responsible for growth impairment remains unclear.…”

“…Eight of them overlap with CNVs defined in other patients with prenatal-onset short stature reported in the DECIPHER (Table 2). Deletions found in patient 1 (22q11.21 deletion), patient 2 (10q26.3 deletion), and patient 3 (4q deletion) overlap with known deletion syndromes (26,27,28). In these CNVs categorized as pathogenic or probably pathogenic, several candidate genes were identified (including one microRNA; Table 2).…”

Aortic dilation, genetic testing, and associated diagnoses

“…In this population some of the diagnoses included major aneuploidies that should be easily [6][7][8][18][19][20][21][22][23][24][25] In many cases, in spite of lacking further supporting clinical evidence of a direct link between AoD and the genes involved in the remaining patients with cytogenetic abnormalities, other potential candidate genes with relationships to cardiac morphogenesis or pathology were identified ( Table 3). [26][27][28][29][30][31][32][33][34][35] We also were able to identify other less common genetic conditions in this population. VACTERL association, which was the most common, has been associated with a variety of heart defects, including BAV and conotruncal defects, but was not typically been associated with AoD in large series of patients.…”

4q- Deletion Syndrome: Psychiatric Symptoms in a Rare Chromosomal Disorder

“…The available research supports the existence of a common phenotype in children with deletions of the long arm of chromosome 4, which is partly explained by epigenetics [4]. A hypothetical partial phenotype-genotype map was made for chromosome 4q, which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes [8]. The evidence in the available articles supports that the molecular characterization of breakpoints is essential for the management of these patients [6].…”