Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions

RP1 truncation variants, including frameshift, nonsense, and splicing, are a common cause of retinitis pigmentosa (RP). RP1 is a unique gene where truncations cause either autosomal dominant RP (adRP) or autosomal recessive RP (arRP) depending on the location of the variants. This study aims to clarify the boundaries between adRP and arRP caused by RP1 truncation variants based on a systemic analysis of 165 RP1 variants from our in-house exome-sequencing data of 7,092 individuals as well as a thorough review of 185 RP1 variants from published literature. In our cohort, potential pathogenic variants were detected in 16 families, including 11 new and five previously described families. Of the 16, seven families with adRP had heterozygous truncations in the middle portion, while nine families with either arRP (eight) or macular degeneration had biallelic variants in the N- and C-terminals, involving 10 known and seven novel variants. In the literature, 147 truncations in RP1 were reported to be responsible for either arRP (85) or adRP (58) or both (four). An overall evaluation of RP1 causative variants suggested three separate regions, i.e., the N-terminal from c.1 (p.1) to c.1837 (p.613), the middle portion from c.1981 (p.661) to c.2749 (p.917), and the C-terminal from c.2816 (p.939) to c.6471 (p.2157), where truncations in the middle portion were associated with adRP, while those in the N- and C-terminals were responsible for arRP. Heterozygous truncations alone in the N- and C- terminals were unlikely pathogenic. However, conflict reports with reverse situation were present for 13 variants, suggesting a complicated pathogenicity awaiting to be further elucidated. In addition, pathogenicity for homozygous truncations around c.5797 and thereafter might also need to be further clarified, so as for missense variants and for truncations located in the two gaps. Our data not only confirmed and refined the boundaries between dominant and recessive RP1 truncations but also revealed unsolved questions valuable for further investigation. These findings remind us that great care is needed in interpreting the results of RP1 variants in clinical gene testing as well as similar features may also be present in some other genes.

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Novel COL11A2 Pathogenic Variants in a Child with Autosomal Recessive Otospondylomegaepiphyseal Dysplasia: A Review of the Literature

Journal of Pediatric Genetics ◽

10.1055/s-0039-1698446 ◽

2019 ◽

Vol 09 (02) ◽

pp. 117-120

Author(s):

Pavalan Selvam ◽

Shekhar Singh ◽

Angita Jain ◽

Herjot Atwal ◽

Paldeep S. Atwal

Keyword(s):

Sequence Analysis ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Review Of The Literature ◽

Pathogenic Variants ◽

Phenotypic Spectrum ◽

Whole Exome ◽

The Family ◽

Type Xi Collagen ◽

Exome Sequence

AbstractOtospondylomegaepiphyseal dysplasia (OSMED) is an inherited autosomal dominant and recessive skeletal dysplasia caused by both heterozygous and homozygous pathogenic variants in COL11A2 encoding the α2(XI) collagen chains, a part of type XI collagen. Here, we describe a 2-year-old girl presenting from birth with a phenotype suggestive of OSMED. On whole exome sequence analysis of the family via commercially available methods, we detected two novel heterozygous pathogenic variants in the proband. In addition, we reviewed the phenotype of autosomal recessive OSMED cases with COL11A2 pathogenic variants reported to date and quantitatively highlighted the phenotypic spectrum.

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Pycnodysostosis: Novel Variants in CTSK and Occurrence of Giant Cell Tumor

Journal of Pediatric Genetics ◽

10.1055/s-0037-1604100 ◽

2017 ◽

Vol 07 (01) ◽

pp. 009-013 ◽

Cited By ~ 2

Author(s):

Hitesh Shah ◽

Mohandas Nair ◽

Krishna Sharan ◽

Dong-Kyu Jin ◽

Sung Cho ◽

...

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Autosomal Recessive ◽

Cathepsin K ◽

Cell Tumor ◽

Exon 2 ◽

Pathogenic Variants ◽

Novel Variants ◽

Intron 4 ◽

Intron 2

AbstractPycnodysostosis is an autosomal recessive skeletal dysplasia caused by pathogenic variants in the cathepsin K (CTSK) gene. We report seven patients from four unrelated families with this condition in whom we have identified three novel pathogenic variants, c.120 + 1G > T in intron 2, c.399 + 1G > A in intron 4, and c.148T > G (p.W50G) in exon 2, and a known variant, c.568C > T (p.Q190*) in exon 5 of CTSK. We present the clinical, radiographic, and molecular findings of all individuals with molecularly proven pycnodysostosis from the present cohort. We also report the occurrence of giant cell tumor in the skull of a patient with this condition.

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The ICR639 CPG NGS validation series: A resource to assess analytical sensitivity of cancer predisposition gene testing

Wellcome Open Research ◽

10.12688/wellcomeopenres.14594.1 ◽

2018 ◽

Vol 3 ◽

pp. 68

Author(s):

Shazia Mahamdallie ◽

Elise Ruark ◽

Esty Holt ◽

Emma Poyastro-Pearson ◽

Anthony Renwick ◽

...

Keyword(s):

Copy Number Variations ◽

Cancer Predisposition ◽

Validation Dataset ◽

Small Scale ◽

Real Sequence ◽

Analytical Sensitivity ◽

Sequencing Data ◽

Pathogenic Variants ◽

Gene Testing ◽

Validation Series

The analytical sensitivity of a next generation sequencing (NGS) test reflects the ability of the test to detect real sequence variation. The evaluation of analytical sensitivity relies on the availability of gold-standard, validated, benchmarking datasets. For NGS analysis the availability of suitable datasets has been limited. Most laboratories undertake small scale evaluations using in-house data, and/or rely on in silico generated datasets to evaluate the performance of NGS variant detection pipelines. Cancer predisposition genes (CPGs), such as BRCA1 and BRCA2, are amongst the most widely tested genes in clinical practice today. Hundreds of providers across the world are now offering CPG testing using NGS methods. Validating and comparing the analytical sensitivity of CPG tests has proved difficult, due to the absence of comprehensive, orthogonally validated, benchmarking datasets of CPG pathogenic variants. To address this we present the ICR639 CPG NGS validation series. This dataset comprises data from 639 individuals. Each individual has sequencing data generated using the TruSight Cancer Panel (TSCP), a targeted NGS assay for the analysis of CPGs, together with orthogonally generated data showing the presence of at least one CPG pathogenic variant per individual. The set consists of 645 pathogenic variants in total. There is strong representation of the most challenging types of variants to detect, with 339 indels, including 16 complex indels and 24 with length greater than five base pairs and 74 exon copy number variations (CNVs) including 23 single exon CNVs. The series includes pathogenic variants in 31 CPGs, including 502 pathogenic variants in BRCA1 or BRCA2, making this an important comprehensive validation dataset for providers of BRCA1 and BRCA2 NGS testing. We have deposited the TSCP FASTQ files of the ICR639 series in the European Genome-phenome Archive (EGA) under accession number EGAD00001004134.

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Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

Neuropediatrics ◽

10.1055/s-0040-1701671 ◽

2020 ◽

Vol 51 (04) ◽

pp. 245-250

Author(s):

Chloé Angelini ◽

Marie Thibaud ◽

Nathalie Aladjidi ◽

Pierre Bessou ◽

Sébastien Cabasson ◽

...

Keyword(s):

Autosomal Recessive ◽

Autosomal Dominant ◽

De Novo ◽

Cutis Laxa ◽

Variable Degree ◽

Severe Phenotype ◽

Pathogenic Variants ◽

Type Iiia ◽

Recessive Type ◽

Neurological Phenotype

AbstractCutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.

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Report of Two Novel Mutations in Indian Patients with Rothmund–Thomson Syndrome

Journal of Pediatric Genetics ◽

10.1055/s-0039-1684017 ◽

2019 ◽

Vol 08 (03) ◽

pp. 163-167

Author(s):

Sakshi Yadav ◽

Seema Thakur ◽

Juergen Kohlhase ◽

Neetu Bhari ◽

Madhulika Kabra ◽

...

Keyword(s):

Autosomal Recessive ◽

Supportive Therapy ◽

Failure To Thrive ◽

Autosomal Recessive Disorder ◽

Skin Lesions ◽

Poor Growth ◽

Pathogenic Variants ◽

Specific Distribution ◽

Novel Variants ◽

Rothmund Thomson Syndrome

AbstractRothmund–Thomson syndrome (RTS) is a rare autosomal recessive disorder caused by mutations in RECQL4 and has characteristic clinical features. We report two unrelated phenotypically diverse patients (cases 1 and 2) with RTS having novel variants in RECQL4 gene. Case-1 was evaluated for poor growth and recurrent fractures and skin lesions. Case-2 presented at 4 months with failure to thrive and radial ray defect and developed poikilodermatous skin lesions after infancy. Both cases were confirmed to have homozygous pathogenic variants in RECQL4. Both patients have normal intellect and are on supportive therapy. The presence of characteristic poikiloderma lesions with specific distribution and skeletal anomalies in a patient with proportionate short stature is a clue toward the diagnosis of RTS.

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Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

Molecular Case Studies ◽

10.1101/mcs.a006130 ◽

2021 ◽

pp. mcs.a006130

Author(s):

Ryan J Patrick ◽

Jill M Weimer ◽

Laura Davis-Keppen ◽

Megan L Landsverk

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Missense Variant ◽

Facial Features ◽

Loss Of Function ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

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Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses

Reproductive Sciences ◽

10.1007/s43032-021-00835-5 ◽

2022 ◽

Author(s):

Zhidan Hong ◽

Xuanyi He ◽

Fang Yu ◽

Huanyu Liu ◽

Xiaoli Zhang ◽

...

Keyword(s):

Autosomal Recessive ◽

Pathological Examination ◽

Compound Heterozygous ◽

Over Expression ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

Novel Variant ◽

Missed Diagnosis

AbstractMeckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive inherited disorder. Missed diagnosis might happen in clinical works due to an unclear genotype–phenotype correlation. We analyzed two families visiting our center; the parents are normal; each of the family aborted a fetus at 12WG. Following ultrasonography and pathological examination, both were diagnosed as MKS. Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. Frameshift mutations in ZNF77 were also detected. Western blot analyzing whole-brain tissue showed that the expression of ZNF77, CC2D2A, and CEP290 was enhanced. HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. Our research provided two novel pathogenic variants of CEP290 and CC2D2A and suggested that ZNF77 might promote the expression of CC2D2A and regulate the amount of SHH.

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Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Neural Plasticity ◽

10.1155/2020/6137083 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Tian-Yi Cui ◽

Xue Gao ◽

Sha-Sha Huang ◽

Yan-Yan Sun ◽

Si-Qi Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Dominant ◽

Asian Population ◽

Nonsyndromic Hearing Loss ◽

Hereditary Hearing Loss ◽

Variant Of Uncertain Significance ◽

Targeted Next Generation Sequencing ◽

Pathogenic Variants ◽

Novel Variants ◽

Uncertain Significance

Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.

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Prevalence and Clinical Features of Autosomal Dominant and Recessive TMC1-Associated Hearing Loss.

10.21203/rs.3.rs-581891/v1 ◽

2021 ◽

Author(s):

Shin-ya Nishio ◽

Shin-ichi Usami

Keyword(s):

Hearing Loss ◽

Clinical Features ◽

Autosomal Recessive ◽

Haplotype Analysis ◽

Autosomal Dominant ◽

Founder Mutation ◽

Family Members ◽

Causative Gene ◽

Pathogenic Variants ◽

Syndromic Hearing Loss

Abstract TMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (DFNA36) and autosomal recessive non-syndromic hearing loss (DFNB7/11). To date, 125 pathogenic variants in TMC1 have been reported. Most of the TMC1 variants are responsible for autosomal recessive hearing loss, with only 7 variants reported as causative for DFNA36. Here we reported the prevalence of TMC1-associated hearing loss in a large non-syndromic hearing loss cohort of about 12,000 subjects. As a result, we identified 26 probands with TMC1-associated hearing loss and the estimated prevalence of TMC1-associated hearing loss in the Japanese hearing loss cohort to be 0.18% among all patients. Among the 26 probands with TMC1-associated hearing loss, 15 cases were identified from autosomal dominant hearing loss families. By using the audiometric data from the probands, family members and previously reported cases, we evaluated the hearing deterioration speed for DFNA36 patients. In addition, we performed haplotype analysis for 11 unrelated autosomal dominant hearing loss families carrying the same variant TMC1: NM_138691:c.1627G > A:p.D543N. The results clearly indicated that the same haplotype was present despite of families being unrelated, supporting the contention that this variant occurred by founder mutation.

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Biallelic variants in the SORD gene are one of the most common causes of hereditary neuropathy among Czech patients

Scientific Reports ◽

10.1038/s41598-021-86857-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

P. Laššuthová ◽

R. Mazanec ◽

D. Staněk ◽

L. Sedláčková ◽

B. Plevová ◽

...

Keyword(s):

Autosomal Recessive ◽

Pcr Primers ◽

Hereditary Neuropathy ◽

Sequencing Data ◽

Pes Cavus ◽

Fragment Analysis ◽

Pathogenic Variants ◽

Common Causes ◽

Specific Amplification ◽

Almost All

AbstractRecently, biallelic variants in the SORD gene were identified as causal for axonal hereditary neuropathy (HN). We ascertained the spectrum and frequency of SORD variants among a large cohort of Czech patients with unknown cause of HN. Exome sequencing data were analysed for SORD (58 patients). The prevalent c.757del variant was tested with fragment analysis (931 patients). Sanger sequencing in additional 70 patients was done. PCR primers were designed to amplify the SORD gene with the exclusion of the pseudogene SORD2P. Sequence differences between gene and pseudogene were identified and frequencies of SNPs were calculated. Eighteen patients from 16 unrelated families with biallelic variants in the SORD gene were found and the c.757del was present in all patients on at least one allele. Three novel, probably pathogenic, variants were detected, always in a heterozygous state in combination with the c.757del on the second allele. Patients presented with a slowly progressive axonal HN. Almost all patients had moderate pes cavus deformity. SORD neuropathy is frequent in Czech patients and the third most common cause of autosomal recessive HN. The c.757del is highly prevalent. Specific amplification of the SORD gene with the exclusion of the pseudogene is essential for a precise molecular diagnostics.

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