Combining exome/genome sequencing with data repository analysis reveals novel gene–disease associations for a wide range of genetic disorders

Abstract

Purpose Within this study, we aimed to discover novel gene–disease associations in patients with no genetic diagnosis after exome/genome sequencing (ES/GS). Methods We followed two approaches: (1) a patient-centered approach, which after routine diagnostic analysis systematically interrogates variants in genes not yet associated to human diseases; and (2) a gene variant centered approach. For the latter, we focused on de novo variants in patients that presented with neurodevelopmental delay (NDD) and/or intellectual disability (ID), which are the most common reasons for genetic testing referrals. Gene–disease association was assessed using our data repository that combines ES/GS data and Human Phenotype Ontology terms from over 33,000 patients. Results We propose six novel gene–disease associations based on 38 patients with variants in the BLOC1S1, IPO8, MMP15, PLK1, RAP1GDS1, and ZNF699 genes. Furthermore, our results support causality of 31 additional candidate genes that had little published evidence and no registered OMIM phenotype (56 patients). The phenotypes included syndromic/nonsyndromic NDD/ID, oral–facial–digital syndrome, cardiomyopathies, malformation syndrome, short stature, skeletal dysplasia, and ciliary dyskinesia. Conclusion Our results demonstrate the value of data repositories which combine clinical and genetic data for discovering and confirming gene–disease associations. Genetic laboratories should be encouraged to pursue such analyses for the benefit of undiagnosed patients and their families.

Further Delineation of Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities Caused by ZNF699 Gene Mutation

“…Bertoli-Avella et al in 2021 reported 13 patients with pathogenic homozygous variants in the ZNF699 gene, improving a genotype-phenotype correlation in autosomal recessive mode of inheritance [ 3 ]. The phenotype is named DEGCAGS syndrome (OMIM 619488) and stands for Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities [ 4 ].…”

Bi‐allelic null variant in matrix metalloproteinase‐15, causes congenital cardiac defect, cholestasis jaundice, and failure to thrive

“…A homozygous deletion of a single nucleotide on chromosome 16 (GRCh37: chr16:58075668del) was found in both patients II.1 and II.2, residing within a shared homozygous region 16q12.2‐2q21 (56223744–64 839 033) (Table 2). 8 Sanger sequencing validation identified both parents as heterozygous carriers for the mutation that was homozygous in patient II.2 (Figure 2B). This variant (NM_002428.2: c.1058delC) was predicted to cause a frameshift in MMP15 reading frame introducing a termination codon after 102 amino acids (p.Pro353Glnfs*102).…”

“…Here, we describe the phenotype of a bi‐allelic frameshift variant in MMP15 identified in two siblings from a consanguineous family who had cardiac defects and other abnormalities 8 . We also reveal the functional consequences of this variant, as well as a missense variant associated with similar clinical manifestations 8 …”

Genetics of Heritable Thoracic Aortic Disease

“…Biallelic variants in the IPO8 gene, encoding the nuclear import protein importin 8, lead to a form of sHTAD presenting with a LDS/SGS-like phenotype with early-onset aortic aneurysms (before 1 year of age in the youngest), marked arterial tortuosity, structural heart disease in involving atrial or ventricular septal defects and patent ductus arteriosus, facial and skeletal anomalies, developmental delay, umbilical and/or inguinal hernias, immune dysregulation and allergic diseases [67][68][69]. No aortic dissection has been reported in a total of 28 patients who have been identified so far, despite a severe aneurysm phenotype in most affected individuals.…”