Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD

AbstractPathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype–phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.

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Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

10.1101/2020.08.24.20179085 ◽

2020 ◽

Author(s):

Riccardo Sangermano ◽

Iris Deitch ◽

Virginie G Peter ◽

Rola Ba-Abbad ◽

Emily M Place ◽

...

Keyword(s):

Retinal Degeneration ◽

Early Onset ◽

Joubert Syndrome ◽

Phenotypic Correlation ◽

Cone Dystrophy ◽

Genetic Modifiers ◽

Retinal Degenerations ◽

Pathogenic Variants ◽

Systemic Disorder ◽

The Impact

Purpose: Pathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity. Methods: Targeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation. Results: Fourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers. Conclusions: The study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

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Phenotype Analysis and Genetic Study of Chinese Patients With Treacher Collins Syndrome

The Cleft Palate-Craniofacial Journal ◽

10.1177/10556656211037509 ◽

2021 ◽

pp. 105566562110375

Author(s):

Meng Lu ◽

Bin Yang ◽

Zixiang Chen ◽

Haiyue Jiang ◽

Bo Pan

Keyword(s):

Rare Variants ◽

Clinical Care ◽

Treacher Collins Syndrome ◽

Chinese Patients ◽

Pathogenic Variants ◽

Premature Termination Codons ◽

Whole Exome ◽

Exome Aggregation Consortium ◽

Phenotype Analysis ◽

Sporadic Cases

Objective The aim of this study was to confirm the pathogenic variants, explore the genotype–phenotype correlation and characteristics of Chinese patients with Treacher Collins syndrome (TCS). Design Clinical details of 3 TCS family cases and 2 sporadic cases were collected and analyzed. Whole-exome sequencing and Sanger sequencing were conducted to detect causative variants. Setting Tertiary clinical care. Patients This study included 8 patients clinically diagnosed with TCS who were from 3 familial cases and 2 sporadic cases. Main Outcome Measures When filtering the database, variants were saved as rare variants if their frequency were less than 0.005 in the 1000 Genomes Project Database, the Exome Aggregation Consortium (ExAC) browser, and the Novogene database, or they would be removed as common ones. The pathogenic variants identified were verified by polymerase chain reaction. The sequencing results were analyzed by Chromas 2.1 software. Results Two novel pathogenic variants (NM_000356.3: c.537del and NM_000356.3: c.1965_1966dupGG) and 2 known pathogenic variants (NM_000356.3: c.1535del, NM_000356.3: c.4131_4135del) were identified within TCOF1 which are predicted to lead to premature termination codons resulting in a truncated protein. There was a known missense SNP (NM_015972.3: c.139G>A) within POLR1D. No phenotype–genotype correlation was observed. Instead, these 8 patients demonstrated the high genotypic and phenotypic heterogeneity of TCS. Conclusions This study expands on the pathogenic gene pool of Chinese patients with TCS. Besides the great variation among patients which is similar to international reports, Chinese patients have their own characteristics in clinical phenotype and pathogenesis mutations.

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Targeted next-generation sequencing (NGS) of germline DNA to identify genetic predisposition to gastric cancer (GC) in patients with CDH1-mutation negative early-onset (EO) or familial GC (FGC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.20 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 20-20

Author(s):

Geoffrey Yuyat Ku ◽

Semanti Mukherjee ◽

Chizoba Okoro ◽

Medha Sharma ◽

Vignesh Ravichandran ◽

...

Keyword(s):

Early Onset ◽

Brca2 Mutation ◽

Clinical Tool ◽

Degree Relative ◽

Targeted Next Generation Sequencing ◽

Pathogenic Variants ◽

Pathogenic Mutations ◽

Sequencing Studies ◽

Predisposition Genes ◽

Cdh1 Mutation

20 Background: While GC arises as part of several hereditary cancer syndromes, a genetic etiology is not identified for most FGC kindreds and EOGC patients. We hypothesize that NGS of germline DNA may reveal previously unsuspected genomic alterations that predispose to EOGC/FGC. Methods: We identified 42 Pts from a prospective GC registry with CDH1-mutation negative EOGC (≤50 years old) and/or with FGC. Germline DNA was analyzed by MSK-IMPACT, a 468-gene targeted NGS panel that includes > 70 genes associated with known cancer predisposition syndromes. GATK HaplotypeCaller (HTC) was used to call SNVs and Indels simultaneously from the sequence read data and joint calling of all samples was used to generate VCF files. We annotated the VCF with public annotators and public allele frequencies from large sequencing studies. Manual variant curation was performed and were classified by ACMG criteria (Genet Med 2015;17:405), with only likely pathogenic and pathogenic variants included. Results: 41 Pts (98%) had early onset and 11 Pts (26%) had FGC (9 had ≥1 1st or 2nd degree relatives with GC). Median age was 40 (range, 18 to 55) and 23 (55%) were men. Ethnicities were 21 (50%) White, 13 (31%) Black, 6 (14%) Asian and 2 (5%) unknown. 40 (95%) had poorly differentiated and/or diffuse histology. Pathogenic mutations were diagnosed in 4 Pts (10%). 1 Pt had a BRCA2 mutation; his father had prostate CA and a paternal aunt had breast CA but he did not meet current NCCN criteria for BRCA testing. Three additional pathogenic mutations were FGFR1, SOX17 and KMT2D; none has previously been described in GC susceptibility but are associated with GC carcinogenesis. All 3 Pts had EOGC. None had FGC but all 3 had ³1 1st-degree relative with CA ( FGFR1: breast, uterine, appendix; SOX17: breast; KMT2D: osteosarcoma). Further functional work of these variants and segregation analysis is on-going. Conclusions: MSK-IMPACT identified germline mutations in 10% of Pts; most are previously not known GC predisposition genes. NGS can be an important clinical tool for screening multiplex families and also a research tool for discovering genes that predispose to GC.

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Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

Genetics in Medicine ◽

10.1038/s41436-021-01116-x ◽

2021 ◽

Author(s):

Suzanne C. E. H. Sallevelt ◽

Alexander P. A. Stegmann ◽

Bart de Koning ◽

Crool Velter ◽

Anja Steyls ◽

...

Keyword(s):

Autosomal Recessive ◽

Rare Variants ◽

Clinical Care ◽

Carrier Testing ◽

Carrier Status ◽

Routine Diagnostics ◽

Affected Offspring ◽

Pathogenic Variants ◽

Increased Risk ◽

Genetics And Genomics

Abstract Purpose Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care. Methods We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported. Results In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring. Conclusion ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

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Novel deep intronic mutation in PLA2G6 causing early-onset Parkinson’s disease with brain iron accumulation through pseudo-exon activation

Neurogenetics ◽

10.1007/s10048-021-00667-0 ◽

2021 ◽

Author(s):

Chiara Cavestro ◽

Celeste Panteghini ◽

Chiara Reale ◽

Alessia Nasca ◽

Silvia Fenu ◽

...

Keyword(s):

Early Onset ◽

Cerebellar Atrophy ◽

Iron Accumulation ◽

Brain Iron ◽

Causative Gene ◽

Coding Regions ◽

Aberrant Transcript ◽

Pathogenic Variants ◽

Intronic Mutation ◽

Mrna Analysis

AbstractPLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.

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High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107347 ◽

2021 ◽

pp. jmedgenet-2020-107347

Author(s):

D Gareth Evans ◽

Elke Maria van Veen ◽

Helen J Byers ◽

Sarah J Evans ◽

George J Burghel ◽

...

Keyword(s):

Breast Cancer ◽

Early Onset ◽

Ductal Carcinoma ◽

Cancer Genes ◽

Early Onset Breast Cancer ◽

Younger Women ◽

Pathogenic Variants ◽

Younger Age ◽

Predisposition Genes

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

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Genetic and immunologic findings in children with recurrent aphthous stomatitis with systemic inflammation

Pediatric Rheumatology ◽

10.1186/s12969-021-00552-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Martina Girardelli ◽

Erica Valencic ◽

Valentina Moressa ◽

Roberta Margagliotta ◽

Alessandra Tesser ◽

...

Keyword(s):

Clinical Diagnosis ◽

Systemic Inflammation ◽

Lupus Erythematosus ◽

Early Onset ◽

Disease Onset ◽

Recurrent Aphthous Stomatitis ◽

Aphthous Stomatitis ◽

Monogenic Disorders ◽

Pathogenic Variants ◽

Targeted Treatments

Abstract Background Recurrent aphthous stomatitis with systemic signs of inflammation can be encountered in inflammatory bowel disease, Behçet’s disease (BD), Systemic Lupus Erythematosus (SLE). In addition, it has been proposed that cases with very early onset in childhood can be underpinned by rare monogenic defects of immunity, which may require targeted treatments. Thus, subjects with early onset recurrent aphthous stomatitis receiving a clinical diagnosis of BD-like or SLE-like disease may deserve a further diagnostic workout, including immunologic and genetic investigations. Objective To investigate how an immunologic, genetic and transcriptomics assessment of interferon inflammation may improve diagnosis and care in children with recurrent aphthous stomatitis with systemic inflammation. Methods Subjects referred to the pediatric rheumatologist for recurrent aphthous stomatitis associated with signs of systemic inflammation from January 2015 to January 2020 were enrolled in the study and underwent analysis of peripheral lymphocyte subsets, sequencing of a 17-genes panel and measure of interferon score. Results We enrolled 15 subjects (12 females, median age at disease onset 4 years). The clinical diagnosis was BD in 8, incomplete BD in 5, BD/SLE overlap in 1, SLE in 1. Pathogenic genetic variants were detected in 3 patients, respectively 2 STAT1 gain of function variants in two patients classified as BD/SLE overlap and SLE, and 1 TNFAIP3 mutation (A20 haploinsufficiency) in patients with BD. Moreover 2 likely pathogenic variants were identified in DNASE1L3 and PTPN22, both in patients with incomplete BD. Interferon score was high in the two patients with STAT1 GOF mutations, in the patient with TNFAIP3 mutation, and in 3 genetic-negative subjects. In two patients, the treatment was modified based on genetic results. Conclusions Although recurrent aphthous stomatitis associated with systemic inflammation may lead to a clinical diagnosis of BD or SLE, subjects with early disease onset in childhood deserve genetic investigation for rare monogenic disorders. A wider genetic panel may help disclosing the genetic background in the subset of children with increased interferon score, who tested negative in this study.

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Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

BMC Medical Genomics ◽

10.1186/s12920-021-01001-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Beatrice Berti ◽

Giovanna Longo ◽

Francesco Mari ◽

Stefano Doccini ◽

Ilaria Piccolo ◽

...

Keyword(s):

Intellectual Disability ◽

Mitochondrial Dysfunction ◽

Early Onset ◽

Integrated Approach ◽

Compound Heterozygous ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

First Case ◽

Spine Mri

Abstract Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.

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P3-017: Rare variants in PLD3 do not increase risk in a belgian cohort of early-onset Alzheimer dementia patients

Alzheimer s & Dementia ◽

10.1016/j.jalz.2015.06.883 ◽

2015 ◽

Vol 11 (7S_Part_13) ◽

pp. P626-P626

Author(s):

Rita Cacace ◽

Tobi Van den Bossche ◽

Sebastiaan Engelborghs ◽

Mathieu Vandenbulcke ◽

Rik Vandenberghe ◽

...

Keyword(s):

Early Onset ◽

Rare Variants ◽

Alzheimer Dementia ◽

Dementia Patients ◽

Increase Risk

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Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants

Diagnostics ◽

10.3390/diagnostics11071218 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1218

Author(s):

Raffaella Brunetti-Pierri ◽

Marianthi Karali ◽

Francesco Testa ◽

Gerarda Cappuccio ◽

Maria Elena Onore ◽

...

Keyword(s):

Wide Spectrum ◽

Clinical Manifestations ◽

Brain Magnetic Resonance Imaging ◽

Joubert Syndrome ◽

Male Adult ◽

Full Field ◽

Pathogenic Variants ◽

Disease Spectrum ◽

Male Individual ◽

The Central Nervous System

Pathogenic variants in the MKS1 gene are responsible for a ciliopathy with a wide spectrum of clinical manifestations ranging from Meckel and Joubert syndrome (JBTS) to Bardet-Biedl syndrome, and involving the central nervous system, liver, kidney, skeleton, and retina. We report a 39-year-old male individual presenting with isolated Retinitis Pigmentosa (RP), as assessed by full ophthalmological evaluation including Best-Corrected Visual Acuity measurements, fundus examination, Goldmann Visual Field test, and full-field Electroretinography. A clinical exome identified biallelic nonsense variants in MKS1 that prompted post-genotyping investigations for systemic abnormalities of ciliopathy. Brain magnetic resonance imaging revealed malformations of the posterior cranial fossa with the ‘molar tooth sign’ and cerebellar folia dysplasia, which are both distinctive features of JBTS. No other organ or skeletal abnormalities were detected. This case illustrates the power of clinical exome for the identification of the mildest forms of a disease spectrum, such as a mild JBTS with RP in the presented case of an individual carrying biallelic truncating variants in MKS1.

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