Clinical and molecular characterization of an emerging chromosome 22q13.31 microdeletion syndrome

Abstract

Microdeletion of chromosome 22q13.31 is a very rare condition. Fourteen patients have been annotated in public databases but, to date, a clinical comparison has not been done and, consequently, a specific phenotype has not been delineated yet. We describe a patient showing neurodevelopmental disorders, dysmorphic features, and multiple congenital anomalies in which SNP array analysis revealed an interstitial 3.15 Mb de novo microdeletion in the 22q13.31 region encompassing 21 RefSeq genes and seven non-coding microRNAs. To perform an accurate phenotype characterization, clinical features observed in previously reported cases of 22q13.31 microdeletions were reviewed and compared to those observed in our patient. To the best of our knowledge, this is the first time that a comparison between patients carrying overlapping 22q13.31 deletions has been done. This comparison allowed us to identify a distinct spectrum of clinical manifestations suggesting that patients with a de novo interstitial microdeletion involving 22q13.31 have an emerging syndrome characterized by developmental delay/intellectual disability, speech delay/language disorders, behavioral problems, hypotonia, urogenital, and hands/feet anomalies. The microdeletion identified in our patient is the smallest reported so far and, for this reason, useful to perform a detailed genotype-phenotype correlation. In particular, we propose the CELSR1, ATXN10, FBLN1, and UPK3A as candidate genes in the onset of the main clinical features of this contiguous gene syndrome. Thus, the patient reported here broadens our knowledge of the phenotypic consequences of 22q13.31 microdeletions facilitating genotype-phenotype correlations. Additional cases are needed to corroborate our hypothesis and confirm genotype-phenotype correlations of this emerging syndrome.

Fraternal twins with Phelan-McDermid syndrome not involving the SHANK3 gene: case report and literature review

“…Based on different analyses of the genes in the 22q13 region [2,7,16] and the pLI score (Additional file 1: Table S1) of these genes, we suggest that the genes CELSR1, ATXN10 and WNT7B are also responsible for the neurodevelopmental clinical features observed in PMS patients, while FBLN1 is a candidate gene that may explain hands/feet anomalies [17]. Our hypothesis is similar to that of Palumbo et al [10]. The functions of the four candidate genes mentioned above are listed in Additional file 3: Document S1.…”

“…The SULT4A1 and PARVB genes have been suggested to be related to neurological features and macrocephaly/hypotonia, respectively [ 9 ]. In addition, Palumbo et al proposed CELSR1 , ATXN10 , FBLN1 , and UPK3A as candidate genes in the onset of the main clinical features of 22q13.31 microdeletion [ 10 ].…”

“…The SHANK3 gene has been identified as the critical candidate gene for the neurological features of this syndrome [2]. However, previous genotype-phenotype studies of PMS [3][4][5][6][7] and several case reports of 22q13 interstitial deletion [8][9][10] have implied the role of additional genes or regulatory regions proximal to the SHANK3 gene in PMS. Here, we report identical clinical and molecular findings from one pair of boy-girl twins with a de novo interstitial 22q13.31-q13.33 deletion not involving the SHANK3 gene.…”

Multi-scale systems genomics analysis predicts pathways, cell types and drug targets involved in normative human cognition variation

“…Multiple lines of evidence suggest that FBLN1 , the gene associated with genome-wide significant SNPs for nonverbal reasoning, is dysregulated in disease. In addition to the evidence provided in our results (Figure 1d, Figure 2c, Supplementary Figure 8,9), FBLN1 has been associated with other rare genetic syndromes and protein levels of FBLN1 have been associated with altered risk for ischaemic stroke 59,60 . However, the mechanism by which FBLN1 contributes to normal brain function is not known.…”

Increasing evidence of hereditary lymphedema caused by CELSR1 loss‐of‐function variants

“…The patient in question showed kidney and heart defects accompanied by slight dysmorphic features, distal abnormalities, and intellectual disability. This patient had a 3.15 Mb de novo microdeletion encompassing more than one gene, although the authors indicate CELSR1 as responsible for certain characteristics of the clinical phenotype (Palumbo et al, ).…”