Online Mendelian Inheritance In Man Genes Research Articles

Investigating gene functions and single-cell expression profiles of de novo variants in orofacial clefts

Orofacial clefts (OFCs) are common congenital birth defects with various etiologies, including genetic variants. Online Mendelian Inheritance in Man (OMIM) annotated several hundred genes involving OFCs. Furthermore, several hundreds of de novo variants (DNVs) have been identified from individuals with OFCs. Some DNVs are related to known OFC genes or pathways, but there are still many DNVs whose relevance to OFC development is unknown. To explore novel gene functions and their cellular expression profiles, we focused on DNVs in genes that were not listed in OMIM. We collected 960 DNVs in 853 genes from published studies and curated these genes, based on the DNVs' deleteriousness, into 230 and 23 genes related to cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), respectively. For comparison, we curated 178 CL/P and 277 CPO genes from OMIM. In CL/P, the pathways enriched in DNV and OMIM genes were significantly overlapped (p= 0.002). Single-cell RNA sequencing (scRNA-seq) analysis of mouse lip development revealed that both gene sets had abundant expression in the ectoderm (DNV genes: adjusted p= 0.032, OMIM genes: adjusted p<0.0002), while only DNV genes were enriched in the endothelium (adjusted p= 0.032). Although we did not achieve significant findings using CPO gene sets, which was mainly due to the limited number of DNV genes, scRNA-seq analysis implicated various expression patterns among DNV and OMIM genes. Our results suggest that combinatory pathway and scRNA-seq data analyses are helpful for contextualizing genes in OFC development.

Global retardation and hereditary spherocytosis associated with a novel deletion of chromosome 8p11.21 encompassing KAT6A and ANK1

The loss of heterozygosity localized at chromosome segment 8p11.2 causes a contiguous gene syndrome, which mostly combined phenotype of Kallmann syndrome and hereditary spherocytosis. It has been documented that this combined phenotype is in association with both the deletion of the fibroblast growth factor receptor 1 (FGFR1) and ankyrin 1 (ANK1) genes. Here, we described a 6-year-old girl with microcephaly, global developmental delay, mental retardation, and hereditary spherocytosis, associated with a heterozygous pathogenic microdeletion of 1.9 Mb size at 8p11.21. Molecular analysis confirmed that the identified microdeletion contained two OMIM (Online Mendelian Inheritance in Man)genes, including ANK1 and lysine acetyltransferase 6 A (KAT6A), but not FGFR1. Therefore, the simultaneous occurrence of mild developmental delay and distinctive facial in this patient was associated with the pathogenic variation of the KAT6A.

Protein-protein interactions underlying the behavioral and psychological symptoms of dementia (BPSD) and Alzheimer's disease.

Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder currently affecting 45 million people worldwide, ranking as the 6th highest cause of death. Throughout the development and progression of AD, over 90% of patients display behavioral and psychological symptoms of dementia (BPSD), with some of these symptoms occurring before memory deficits and therefore serving as potential early predictors of AD-related cognitive decline. However, the biochemical links between AD and BPSD are not known. In this study, we explored the molecular interactions between AD and BPSD using protein-protein interaction (PPI) networks built from OMIM (Online Mendelian Inheritance in Man) genes that were related to AD and two distinct BPSD domains, the Affective Domain and the Hyperactivity, Impulsivity, Disinhibition, and Aggression (HIDA) Domain. Our results yielded 8 unique proteins for the Affective Domain (RHOA, GRB2, PIK3R1, HSPA4, HSP90AA1, GSK3beta, PRKCZ, and FYN), 5 unique proteins for the HIDA Domain (LRP1, EGFR, YWHAB, SUMO1, and EGR1), and 6 shared proteins between both BPSD domains (APP, UBC, ELAV1, YWHAZ, YWHAE, and SRC) and AD. These proteins might suggest specific targets and pathways that are involved in the pathogenesis of these BPSD domains in AD.

Clinical and genetic analysis of a child with chromosomal 13q32.1-q33.3 deletion

To explore the genetic etiology of a child with moderate mental retardation and multiple malformations. The child and his parents underwent conventional G banding karyotype analysis and single nucleotide polymorphism-based mircoarray (SNP-array) scan. A systematic review for chromosome 13q deletions was also conducted to explore the correlation between genotype and clinical phenotypes. G banding karyotype of the child showed a partial deletion in the long arm of chromosome 13 described as 46,XY,del(13)(q32). SNP-array detected a deletion fragment of 11.367 Mb in 13q32.1-q33.3 region, which encompassed 30 OMIM (Online Mendelian Inheritance in Man) genes including FARP1, STK24 and ZIC2. The parents were found with no obvious abnormality in their karyotypes and SNP-array results, suggesting a de novo origin for the deletion. Combined with previous reported cases, chromosomal 13q deletions seem to have various pathogenic effects on the patients. Chromosomal 13q32.1-q33.3 deletion probably underlies the disease phenotype in the child, and EFNB2 may be a candidate gene for congenital heart defect, genital malformation, hypospadias and anorectal malformations.

Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis.

Bleeding assessment tools and laboratory phenotyping often remain inconclusive in patients with a haemorrhagic diathesis. To describe the phenotype and genetic profile of patients with a bleeding tendency. Whole exome sequencing (WES) was incorporated in the routine diagnostic pathway of patients with thrombocytopenia (n=17), platelet function disorders (n=19) and an unexplained bleeding tendency (n=51). The analysis of a panel of 126 OMIM (Online Mendelian Inheritance in Man) genes involved in thrombosis and haemostasis was conducted, and if negative, further exome-wide analysis was performed if informed consent given. Eighteen variants were detected in 15 patients from a total of 87 patients (17%). Causative variants were observed in MYH9 (two cases), SLFN14, P2RY12 and GP9. In addition, one case was considered solved due to combined carriership of F7 and F13A1 variants and one with combined carriership of F2, F8 and VWF, all variants related to secondary haemostasis protein aberrations. Two variants of uncertain significance (VUS) were found in two primary haemostasis genes: GFI1B and VWF. Eight patients were carriers of autosomal recessive disorders. Exome-wide analysis was performed in 54 cases and identified three variants in candidate genes. Based on our findings, we conclude that performing WES at the end of the diagnostic trajectory can be of additive value to explain the complete bleeding phenotype in patients without a definite diagnosis after conventional laboratory tests. Discovery of combinations of (novel) genes that predispose to bleeding will increase the diagnostic yield in patients with an unexplained bleeding diathesis.

Genetic testing and prenatal diagnosis of X-linked ichthyosis in two pedigrees

Objective To analyze genetic testing and prenatal diagnosis of two pedigrees with X-linked ichthyosis. Methods Karyotyping, bacterial artificial chromosomes-on-BeadsTM (BoBs), fluorescence in situ hybridization (FISH) and single nucleotide polymorphism array (SNP-array) were used to detect amniotic fluid and peripheral blood specimens of two pedigrees, one with and one without known family history of ichthyosis. Clinical data was collected and analyzed as well. Results (1) The pedigree without known family history: Prenatal BoBs showed that the XC1 probe of fetusⅣ-12 was from 0.36 to 0.50, suggesting the presence of microdeletion. SNP-array analysis of gravidaⅢ-13 showed a 1.68 Mb copy number deletion at Xp22.31 and four missing Online Mendelian Inheritance in Man (OMIM) genes (HDHD1, STS, VCX and PNPLA4). Fetal SNP-array revealed a deletion of arr[hg19] Xp22.31 (6 455 151-8 135 644)×0, indicating a maternally inherited one. FISH analysis verified the deletion in STS gene in fetus Ⅳ-12, whose karyotype was 46, XY. The gravida's female cousin (Ⅲ-21) and nephew (Ⅳ-14) also had STS gene deletion, which size was the same as that from the gravida and the fetus. Fetus (Ⅳ-12) was delivered at term by cesarean section with normal skin, but an extensive white scales appeared on the abdomen one week after birth and the symptom was aggravated when the weather was dry. The infant was followed up to eight months old and no other clinical symptoms were found. (2) The pedigree with known family history: SNP-array revealed that a 1.2 Mb copy number deletion at Xp22.31 and four missing OMIM genes (HDHD1, STS, VCX and PNPLA4) were detected in pregnant women (Ⅲ-21), proband (Ⅳ-16) and fetus (Ⅳ-17). FISH analysis of the fetus verified the deletion in STS gene. The karyotype of the fetus was 46, XY. FetusⅣ-17 was delivered at term by cesarean section with normal skin, but white scales widely appeared on the abdomen ten days after birth. The infant was followed up to four months old and no other clinical symptoms were found. Conclusion Molecular genetic techniques such as BoBs, FISH and SNP-array are used in combination in this study to provide genetic testing and prenatal diagnosis to two XLI pedigrees, which is helpful for clinical diagnosis and genetic counseling. Key words: Ichthyosis, X-linked; Pedigree; Steryl-sulfatase; Prenatal diagnosis; Genetic testing

Prenatal diagnosis of familial transmission of 17q12 microduplication associated with no apparent phenotypic abnormality

ObjectiveWe present prenatal diagnosis of familial transmission of 17q12 duplication associated with no apparent phenotypic abnormality. Case ReportA 36-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Cytogenetic analysis revealed a karyotype of 46,XY. Array comparative genomic hybridization of uncultured amniocytes revealed a 1.42-Mb duplication of 17q12 or arr 17q12 (34,822,465–36,243,365) × 3 encompassing 12 Online Mendelian Inheritance in Man (OMIM) genes including LHX1, ACACA, and HNF1B. Array comparative genomic hybridization analysis of parental bloods revealed no genomic imbalance in the mother, and a result of arr 17q12 (34,611,377–36,248,889) × 2.9 encompassing 16 OMIM genes, including LHX1, ACACA, and HNF1B, in the 29-year-old phenotypically normal father. Prenatal ultrasound findings were unremarkable. The parents elected to continue the pregnancy. At 37 weeks of gestation, a 2789-g normal male baby was delivered uneventfully. When examined at the age of 7 months, the neonate was as phenotypically normal as his father. ConclusionThe 17q12 microduplication may present with variable phenotypes including no apparent phenotypic abnormality in familial cases. However, neuropsychiatry assessment and monitoring should be warranted in childhood and through adulthood under such a circumstance.