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Bardet‐Biedl syndrome (BBS), a rare primary form of ciliopathy, with heterogeneous clinical and genetic presentation is characterized by rod cone dystrophy, obesity, polydactyly, urogenital abnormalities, and cognitive impairment. Here, we delineate the genetic profile in a cohort of 108 BBS patients from India by targeted gene sequencing‐based approach for a panel of ciliopathy (including BBS) and other inherited retinal disease genes. We report here a higher frequency of BBS10 and BBS1 gene variations. A different spectrum of variations including a putatively novel gene TSPOAP1, for BBS was identified. Increased percentage frequency of digenic variants (36%) in the disease cohort, role of modifiers in familial cases are some of the salient observations in this work. This study appends the knowledge of BBS genetics pertaining to patients from India. We observed a different molecular epidemiology of BBS patients in this study cohort compared to other reports, which emphasizes the need for molecular testing in affected patients. [ABSTRACT FROM AUTHOR]

Objectives: Due to upcoming gene‐specific therapy approaches for ALS patients, understanding familial and sporadic ALS genetics is becoming increasingly important. In this study, we wanted to investigate underlying genetic causes for an SALS patient. Methods: We performed ALS gene panel sequencing and subsequent segregation analysis in the family. Results: Genetic studies suggest that a proportion of SALS cases has an oligogenic origin due to the combination of low‐effect size mutations in several ALS genes. Maximally three mutations in different ALS disease genes have been described in isolated ALS patients. Here, we report for the first time the co‐occurrence of rare nonsynonymous variants in four known ALS genes in a SALS patient (c.859G > A/p.Gly287Ser in TARDBP, c.304G > T/p.Glu102* in NEK1, c.3446C > A/p.Gly1149Val in ERBB4, and c.1015C > T/p.Arg339Trp in VEGFA). All four variants were unique for the patient, whereas up to three of these variants were detected in the unaffected family members, all older than the patient. Discussion: Our study suggests that SALS can be caused by the additive or synergistic action of low‐effect size mutations. Broader use of gene panel analysis or whole exome/genome sequencing may reveal a potentially treatable oligogenic causation in a higher percentage of SALS than previously thought. [ABSTRACT FROM AUTHOR]

Background: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). Objectives: We aimed to conduct an exome‐wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP. Methods: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole‐exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls. Results: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24–6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49–13.07, P = 0.005). Similar results were obtained after including only genetically‐undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05–365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7‐interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. Conclusions: Our results provide evidence for complex inheritance in SPG7‐associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Idiopathic hypogonadotropic hypogonadism (IHH) can be divided into two major forms, normosmic IHH and Kallmann syndrome (KS). Genetic mutations are responsible for the majority of IHH. PLXNA1 has recently been implicated in the GnRH neuron migration and the etiology of KS. We aimed to investigate the prevalence and associated phenotypes of PLXNA1 variants in a large cohort of IHH patients. We screened the whole exome data of 215 IHH patients in a single center for causative PLXNA1 variants. Our studies showed eight novel (p.Arg836His, p.Lys1451Arg, p.Val287Met, p.Val536Ile, p.Ser1850Arg, p.Ile1701Val, p.Arg319Trp, and p.Pro485Leu) and two previously described (p.Arg528Trp and p.Gly720Glu) heterozygous PLXNA1 variants in nine affected individuals from seven unrelated families. Only three of nine patients were anosmic (KS) while the remaining patients showed normal olfactory function (nIHH). Seven of nine patients (77.7%) harbored additional one or two variants in other nIHH/KS‐associated genes, including PROKR2, IGSF10, HS6ST1, SEMA3E, CCDC141, FGFR1, NRP1, POLR3A, and SRA1. Our findings indicate that PLXNA1 variants cause not only anosmic but also normosmic IHH with a relatively high prevalence (3.9%). Heterozygous missense PLXNA1 variants appear to be involved together with other IHH gene variants in bringing about the IHH disease phenotype. Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotrpic hypogonadism. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia (CDH) is a relatively common, life-threatening birth defect. We present a family with recurrent CDH-paraesophageal and central-for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p.Ile1657Asnfs*30) in the fibrillin 1 gene ( FBN1) that causes Marfan syndrome. A diagnosis of Marfan syndrome had not been considered previously in this family. However, a review of the literature demonstrated that FBN1 mutations have an unusual pattern of CDH in which paraesophageal hernias are particularly common. Subsequent clinical evaluations revealed evidence for ectopia lentis in affected family members supporting a clinical diagnosis of Marfan syndrome. Since only two other cases of familial CDH have been described in association with FBN1 mutations, we investigated an oligogenic hypothesis by examining ES data for deleterious sequence changes in other CDH-related genes. This search revealed putatively deleterious sequence changes in four other genes that have been shown to cause diaphragm defects in humans and/or mice- FREM1, DES, PAX3 and MET. It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. However, their individual contribution is likely to be small compared to that of the frameshift mutation in FBN1. We conclude that ES can be used to identify both major and minor genetic factors that may contribute to CDH. These results also suggest that ES should be considered in the diagnostic evaluation of individuals and families with CDH, particularly when other diagnostic modalities have failed to reveal a molecular etiology. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Potato progenies in a line × tester mating design and the clonal parents were screened for field resistance to potato leafroll virus (PLRV) to determine the heritability of this trait. Twelve advanced potato clones or varieties were crossed as pistillate parents to two pollen testers. The seedling progenies and clonal parents were exposed to aphid-transmitted potato leafroll virus for two growing seasons. Cumulative infection by potato leafroll virus was determined by post-season serological indexing of foliage grown from sprouted tubers after 2 years of exposure. Narrow-sense heritability was estimated from regression of mid-parent on progeny as h² = 0.72. This estimate indicates a high level of useable genetic variance for PLRV resistance in advanced breeding materials. Although variation in resistance to PLRV appears to be a quantitative trait in susceptible and moderately resistant clones, performance of the most resistant parents suggests that genes with major effects may be present. These results are similar to the conclusions of other researchers who found one or two genes controlling the phenotypes of extreme resistance, resistance to infection, or suppression of virus titre. [ABSTRACT FROM AUTHOR]

Holoprosencephaly (HPE) is a complex genetic disorder of the developing forebrain characterized by high phenotypic and genetic heterogeneity. HPE was initially defined as an autosomal dominant disease, but recent research has shown that its mode of transmission is more complex. The past decade has witnessed rapid development of novel genetic technologies and significant progresses in clinical studies of HPE. In this review, we recapitulate genetic epidemiological studies of the largest European HPE cohort and summarize the novel genetic discoveries of HPE based on recently developed diagnostic methods. Our main purpose is to present different inheritance patterns that exist for HPE with a particular emphasis on oligogenic inheritance and its implications in genetic counseling., (© 2018 Wiley Periodicals, Inc.)

We have ascertained two families affected with familial amyotrophic lateral sclerosis (ALS) in which they both carry a hexanucleotide repeat expansion in the C9orf72 gene, specifically in individuals who also presented with frontotemporal dementia (FTD) or behavioral variant FTD (bvFTD). While some reports attribute this phenotypic heterogeneity to the C9orf72 expansion alone, we screened for additional genetic variation in known ALS-FTD genes that may also contribute to or modify the phenotypes. We performed genetic testing consisting of C9orf72 hexanucleotide expansion, ATXN2 polyglutamine (polyQ) expansion, and targeted next generation sequencing using the ONDRISeq, a gene panel consisting of 80 genes known to be associated with neurodegenerative diseases such as ALS, FTD, Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment. In addition to the C9orf72 expansion, we observed an ATXN2 polyQ intermediate length expansion, and OPTN p.Met468Arg in patients who exhibited ALS and FTD or bvFTD. We conclude that the C9orf72 expansion likely explains much of the ALS-FTD phenotype; however, inheritance of these additional variants likely modifies the disease course and may provide further evidence for biologically relevant oligogenic inheritance in ALS., (© 2017 Wiley Periodicals, Inc.)