Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family

The signal-induced proliferation-associated 1-like 3 (SIPA1L3) gene that encodes a putative Rap GTPase-activating protein (RapGAP) has been associated with congenital cataract and eye development abnormalities. However, our current understanding of the mutation spectrum of SIPA1L3 associated with eye defects is limited. By using whole-exome sequencing plus Sanger sequencing validation, we identified a novel heterozygous c.1871A > G (p.Lys624Arg) variation within the predicted RapGAP domain of SIPA1L3 in the proband with isolated juvenile-onset cataracts from a three-generation Chinese family. In this family, the proband's father and grandmother were also heterozygous for the c.1871A > G variation and affected by cataracts varying in morphology, severity, and age of onset. Sequence alignment shows that the Lys 624 residue of SIPA1L3 is conserved across the species. Based on the resolved structure of Rap1–Rap1GAP complex, homology modeling implies that the Lys 624 residue is structurally homologous to the Lys 194 of Rap1GAP, a highly conserved lysine residue that is involved in the interface between Rap1 and Rap1GAP and critical for the affinity to Rap·GTP. We reasoned that arginine substitution of lysine 624 might have an impact on the SIPA1L3-Rap·GTP interaction, thereby affecting the regulatory function of SIPA1L3 on Rap signaling. Collectively, our finding expands the mutation spectrum of SIPA1L3 and provides new clues to the molecular mechanisms of SIPA1L3-related cataracts. Further investigations are warranted to validate the functional alteration of the p.Lys624Arg variant of SIPA1L3.

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Biallelic Mutations in WDR12 is Associated With Male Infertility With Tapered-Head Sperm

10.21203/rs.3.rs-817537/v1 ◽

2021 ◽

Author(s):

juan hua ◽

Lan Guo ◽

Yao Yao ◽

Yangyang Wan ◽

Wen Hu ◽

...

Keyword(s):

Male Infertility ◽

Molecular Mechanisms ◽

Missense Variant ◽

Bioinformatic Analysis ◽

Chinese Family ◽

Intense Staining ◽

Whole Exome ◽

Repeat Domain ◽

Biallelic Mutations ◽

Pachytene Spermatocytes

Abstract Teratozoospermia is a rare disease associated with male infertility. Unfortunately, approximately 30% of the genetic causes associated with teratozoospermia remain unknown. Several recurrent genetic mutations have been reported to be associated with globozoospermia, macrozoospermia and acephalic spermatozoa, whereas the genetic basis of tapered-head sperm is relatively less well-understood. In this study, whole-exome sequencing (WES) identified a homozygous WD repeat domain 12 (WDR12) (p.Ser162Ala/c.484T>G) variant in an infertile patient with tapered-head sperm from a consanguineous Chinese family. Bioinformatic analysis predicted this mutation to be a pathogenic variant. To further verify the effect of this variant, we analyzed WDR12 protein expression in the patient’s spermatozoa by western blot and found WDR12 to be significantly down-regulated. Also, we found that WDR12 expression is increased in pachytene spermatocytes, and intense staining was visible throughout the round spermatids in mouse testis. Based on our results, we concluded that a rare biallelic pathogenic missense variant (p.Ser162Ala/c.484T>G) in the WDR12 gene causes teratozoospermia. These results will provide novel insights into understanding the molecular mechanisms of male infertility and will help clinicians provide accurate diagnoses.

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Heterozygous missense RAD21 variant in a peripheral sclerocornea pedigree

10.1101/547547 ◽

2019 ◽

Cited By ~ 1

Author(s):

Bi Ning Zhang ◽

Tommy Chung Yan Chan ◽

Pancy Oi Sin Tam ◽

Yu Liu ◽

Chi Pui Pang ◽

...

Keyword(s):

Cell Lines ◽

Genetic Variant ◽

Mrna Level ◽

Missense Variant ◽

Genetic Alterations ◽

Chinese Family ◽

Wild Type ◽

Whole Exome ◽

Rare Congenital Disorder ◽

Corneal Diameter

AbstractBackgroundSclerocomea is a rare congenital disorder characterized with cornea opacification. We identified a heterozygous missense RAD21 variant in a non-cons anguineous Chinese family with multiple peripheral sclerocomea patients spanning across three generations inherited in an autosomal dominant manner.MethodsComprehensive ophthalmic examinations were conducted on all 14 members. Whole exome sequencing was used to identify the genetic alterations in the affected pedigree members. Lymphoblastoid cell lines (LCLs) were established using blood samples from all members. Cleavage of RAD21 protein was quantified in these cell lines.ResultsAll affected individuals showed features of scleralization over the peripheral cornea of both eyes. Mean horizontal and vertical corneal diameter were significantly decreased in the affected members. Significant differences were also observed on mean apex pachymetry between affected and unaffected subjects. A RAD21C1348T variant was co-segregated with affected members. Both the wild-type allele and the missense variant were expressed at the mRNA level. This variant caused RAD21 R450C substitution at the separase cleavage site, which led to reduced RAD21 cleavage.ConclusionWe believe this is the first report of genetic variant in sclerocornea without other syndromes. Further work is needed to confirm the RAD21R450C variant with sclerocomea.

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Heterozygous FMN2 Missense Variant Found in A Family Case of Premature Ovarian Insufficiency

10.21203/rs.3.rs-832452/v1 ◽

2021 ◽

Author(s):

Jie Li ◽

Tianliu Peng ◽

Le Wang ◽

Panpan Long ◽

Ruping Quan ◽

...

Keyword(s):

Exome Sequencing ◽

Low Frequency ◽

Missense Variant ◽

Sporadic Case ◽

Premature Ovarian Insufficiency ◽

Chinese Family ◽

Ovarian Insufficiency ◽

Mutant Type ◽

Pathogenic Genes ◽

Whole Exome

Abstract Background Premature Ovarian Insufficiency plagues 1% of women under 40, while quite a few remain an unknown cause. The development of sequencing has helped find pathogenic genes and reveal the relationship between DNA repair and ovarian reserve. Through the exome sequencing, our study targets screening out the possible POI pathogenic gene and variants in a Chinese family and 20 sporadic POI patients, preliminarily exploring the functional impact and finding out potential linkages between the gene and POI. Results The whole exome sequencing suggested a novel FMN2 heterozygous variant c.1949C > T (p.Ser650Leu) carried by all three patients in a Chinese family and another c.1967G > A(p.Arg656His) variant in a sporadic case. Since no FMN2 missense mutation is reported for causing human POI, we preliminarily assessed p.Ser650Leu variant via cross-species alignment and 3D modeling and found it possibly deleterious. A series of functional evidence was consistent with our hypothesis. We proved the expression of FMN2 in different stages of oocytes and observed a statistical difference of chromosomal breakages between the POI patient carrying p.Arg656His variant and the health control (p = 0.0013). Western Blot also suggested a decrease in FMN2 and P21 in the mutant type and an associated increase in H2AX. The p.Arg656His variant with an extremely low frequency also indicated that the gene FMN2 might play an essential role in the genetic etiology of POI. To the best of our knowledge, this is the first POI report on missense variants of FMN2. Conclusion This finding indicates a novel gene possibly related to POI and sheds lights on the study of FMN2.

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Novel Homozygous TULP1 and RPE65 Variants Underlies Recessive Retinitis Pigmentosa

10.20944/preprints202009.0062.v1 ◽

2020 ◽

Author(s):

Amjad Khan ◽

Xiao Bai ◽

Muhammad Umair ◽

Shirui Han ◽

Xiaerbati Habulieti ◽

...

Keyword(s):

Data Analysis ◽

Retinitis Pigmentosa ◽

Molecular Mechanisms ◽

Mutation Screening ◽

Missense Variant ◽

Disease Phenotype ◽

Whole Exome ◽

Retinal Disorders ◽

Pakistani Families ◽

Inherited Retinal Disorders

Retinitis pigmentosa (RP) clinically and genetically heterogeneous group of inherited retinal disorders (IRD) that result in retinal degeneration. This study aimed to identify the genetic findings of patients with autosomal recessive retinitis pigmentosa (arRP). Whole exome sequencing (WES) was performed in two unrelated Pakistani families underlying arRP. Data analysis and mutation screening was performed for all the known RP genes following bi-directional Sanger sequencing to determine whether any of the candidate variants co-segregated with the disease phenotype in the families. WES data analysis revealed a novel homozygous missense variant (c.1274T>C) in the in Tubby like Protein 1 (TULP1 NM_003322.6) gene in family 1 and a novel homozygous frameshift variant (c.351delC) in the retinoid isomerohydrolase 65 (RPE65 NM_000329.3) gene in family 2. The identified variants perfectly co-segregated with the disease phenotype within the families. Our results strongly suggest that mutations in TULP1 and RPE65 are responsible for the retinal phenotype in the affected individuals. These mutations will increase the mutation spectrum of these genes; furthermore, it will enhance our knowledge and understanding of the underlying molecular mechanisms of retinitis pigmentosa.

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A Novel Missense Variant of TP63 Heterozygously Present in Split-Hand/Foot Malformation

BioMed Research International ◽

10.1155/2020/4215632 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Hao Geng ◽

Dongdong Tang ◽

Chuan Xu ◽

Xiaojin He ◽

Zhiguo Zhang

Keyword(s):

Blood Sample ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Peripheral Blood ◽

Sanger Sequencing ◽

Missense Variant ◽

Chinese Family ◽

Peripheral Blood Sample ◽

Whole Exome ◽

Novel Variant

Background. Split-hand/foot malformation (SHFM) is a severe congenital disability mainly characterized by the absence or hypoplasia of the central ray of the hand/foot. To date, several candidate genes associated with SHFM have been identified, including TP63, DLX5, DLX6, FGFR1, and WNT10B. Herein, we report a novel variant of TP63 heterozygously present in affected members of a family with SHFM. Methods. This study investigated a Chinese family, in which the proband and his son suffered from SHFM. The peripheral blood sample of the proband was used to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Postsequencing bioinformatic analyses and Sanger sequencing were conducted to verify the identified variants and parental origins on all family members in the pedigree. Results. By postsequencing bioinformatic analyses and Sanger sequencing, we identified a novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in this family that results in a substitution of methionine with isoleucine, which is probably associated with the occurrence of SHFM. Conclusion. A novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in SHFM was thus identified, which may enlarge the spectrum of known TP63 variants and also provide new approaches for genetic counselling of families with SHFM.

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Disruption of PIKFYVE causes congenital cataract in human and zebrafish

eLife ◽

10.7554/elife.71256 ◽

2022 ◽

Vol 11 ◽

Author(s):

Shaoyi Mei ◽

Yi Wu ◽

Yan Wang ◽

Yubo Cui ◽

Miao Zhang ◽

...

Keyword(s):

Congenital Cataract ◽

Molecular Mechanisms ◽

Kinase Domain ◽

Dominant Negative ◽

Chinese Family ◽

Bafilomycin A1 ◽

Atpase Inhibitor ◽

Causative Gene ◽

Whole Exome ◽

Pathological Variant

Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. However, the molecular mechanisms underlying the pathogenesis of congenital cataract remain incompletely defined. Through whole-exome sequencing of a Chinese family with congenital cataract, we identified a potential pathological variant (p.G1943E) in PIKFYVE, which is located in the PIP kinase domain of the PIKFYVE protein. We demonstrated that heterozygous/homozygous disruption of PIKFYVE kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKFYVE activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and pinpointed the potential application of Baf-A1 for the treatment of congenital cataract caused by PIKFYVE deficiency.

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Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

Disease Markers ◽

10.1155/2020/8360841 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Tahir Zaib ◽

Chunhui Zhang ◽

Komal Saleem ◽

Lidan Xu ◽

Qian Qin ◽

...

Keyword(s):

Lynch Syndrome ◽

Functional Characterization ◽

Family Members ◽

Missense Variant ◽

Chinese Family ◽

Causative Gene ◽

Bioinformatic Tools ◽

Whole Exome

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRCs) inherited in an autosomal-dominant manner. Here, we reported a multigeneration Chinese family clinically diagnosed with LS according to the Amsterdam II criteria. To identify the underlying causative gene for LS in this family, whole-exome sequencing (WES) was performed. A germline missense variant (c.2054C>T:p.S685F) in exon 18 of MLH1 was successfully identified by WES. Sanger sequencing verified the results of WES and also confirmed the cosegregation of the MLH1 missense variant in all affected members of the family including two unaffected family members. Bioinformatic tools predicted the identified MLH1 variant as deleterious. Immunohistochemistry (IHC) staining showed loss of MLH1 and PMS2 protein expression. In vitro expression analysis also revealed that the identified MLH1 missense variant (c.2054C>T:p.S685F) results in reduced expression of both MLH1 and PMS2 proteins. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, the missense mutation c.2054C>T in MLH1 was classified as a “pathogenic” variant. Two unaffected family members were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years as both were at higher risk of LS. In conclusion, our findings widen the genotypic spectrum of MLH1 mutations responsible for LS. This study increases the phenotypic spectrum of LS which will certainly help the clinicians in diagnosing LS in multigeneration families. This study also puts emphasis on the importance of genetic counselling for the benefit of asymptomatic carriers of MMR gene variants who are at higher risk of LS.

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A novel variant of IHH in a Chinese family with brachydactyly type 1

10.21203/rs.2.11651/v2 ◽

2019 ◽

Author(s):

Qi Yang ◽

Jin Wang ◽

Xiaoxian Tian ◽

Fei Chen ◽

Jing Lan ◽

...

Keyword(s):

Autosomal Dominant ◽

Missense Variant ◽

Chinese Family ◽

Indian Hedgehog ◽

Autosomal Dominant Disorder ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variant ◽

Active Fragment

Abstract Brachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog ( IHH ). The disorder is mainly characterized by shortening or missing of the middle phalanges. The following study revealed a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene after performing whole-exome sequencing in the proband of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the variants on IHH gene which contribute to the cause of BDA-1.

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Identification of a Novel Variant of ARHGAP29 in a Chinese Family with Nonsyndromic Cleft Lip and Palate

BioMed Research International ◽

10.1155/2020/8790531 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Jian-Xia Tang ◽

Xiang-Shui Xiao ◽

Kai Wang ◽

Jie-Yuan Jin ◽

Liang-Liang Fan ◽

...

Keyword(s):

Cleft Lip ◽

Cleft Lip And Palate ◽

Genetic Diagnosis ◽

Missense Variant ◽

Bioinformatic Analysis ◽

Chinese Family ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variant ◽

Development Methods

Background. Cleft lip with or without cleft palate (CL/P) is the most common facial birth defect, with a worldwide incidence of 1 in 700-1000 live births. CL/P can be divided into syndromic CL/P (SCL/P) and nonsyndromic CL/P (NSCL/P). Genetic factors are an important component to the etiology of NSCL/P. ARHGAP29, one of the NSCL/P disease-causing genes, mediates the cyclical regulation of small GTP binding proteins such as RhoA and plays an essential role in cellular shape, proliferation, and craniofacial development. Methods. The present study investigated a Chinese family with NSCL/P and explored potential pathogenic variants using whole-exome sequencing (WES). Variants were screened and filtered through bioinformatic analysis and prediction of variant pathogenicity. Cosegregation was subsequently conducted. Results. We identified a novel heterozygous missense variant of ARHGAP29 (c.2615C > T, p.A872V) in a Chinese pedigree with NSCL/P. Conclusion. We detected the disease-causing variant in this NSCL/P family. Our identification expands the genetic spectrum of ARHGAP29 and contributes to novel approaches to the genetic diagnosis and counseling of CL/P families.

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