A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations

Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies had unilateral or bilateral retina dysplasia and/or optic nerve hypoplasia. The four litters shared the same father or grandfather suggesting a heritable condition with an autosomal dominant mode of inheritance. The genome of one affected dog was sequenced and compared to 601 control genomes. A heterozygous private nonsense variant, c.487C>T, was found in the SIX6 gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*). We genotyped all available family members and 464 unrelated Golden Retrievers. All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases. The SIX6 protein is a homeobox transcription factor with a known role in eye development. In humans and other species, SIX6 loss of function variants were reported to cause congenital eye malformations. This strongly suggests that the c.487C>T variant detected contributed to the observed eye malformations. We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs.

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A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

Cell Death and Disease ◽

10.1038/s41419-021-03636-5 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Joanne M. Hildebrand ◽

Bernice Lo ◽

Sara Tomei ◽

Valentina Mattei ◽

Samuel N. Young ◽

...

Keyword(s):

Potential Role ◽

Autosomal Dominant ◽

Inflammatory Diseases ◽

Diabetic Patients ◽

Incomplete Penetrance ◽

Loss Of Function ◽

Healthy Sibling ◽

Dominant Disease ◽

Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

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A combined in silico, in vitro and clinical approach to characterise novel pathogenic missense variants in PRPF31 in retinitis pigmentosa

10.1101/480343 ◽

2018 ◽

Author(s):

Gabrielle Wheway ◽

Liliya Nazlamova ◽

Nervine Meshad ◽

Samantha Hunt ◽

Nicola Jackson ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

In Silico ◽

Autosomal Dominant ◽

Missense Variant ◽

Incomplete Penetrance ◽

Clinical Approach ◽

Loss Of Function ◽

Autosomal Dominant Retinitis Pigmentosa ◽

Missense Variants

AbstractAt least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localise to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood.In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T>A, p.Ile114Asn.This work demonstrates how in silico modelling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.

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Familial Phonological Disorders

Journal of Speech and Hearing Disorders ◽

10.1044/jshd.5501.160 ◽

1990 ◽

Vol 55 (1) ◽

pp. 160-170 ◽

Cited By ~ 27

Author(s):

Barbara A. Lewis

Keyword(s):

Learning Disabilities ◽

Autosomal Dominant ◽

Threshold Model ◽

Family Members ◽

Speech Disorders ◽

Dominant Mode ◽

Incomplete Penetrance ◽

Phonological Disorders ◽

Language Problems ◽

Mode A

The pedigrees of 4 children with a severe phonological disorder demonstrating three generations of members with speech/language problems are presented. All 4 probands were female with two mothers, two fathers, and five out of six siblings affected. All pedigrees contained family members with dyslexia and learning disabilities as well as speech disorders. Family members varied in the type of speech problems that they demonstrated and the severity of their disorder, thus suggesting variable expressivity and incomplete penetrance. An autosomal dominant mode, a multifactorial-polygenic model, and a sex-specific threshold model for expression are discussed.

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IRF4 haploinsufficiency in a family with Whipple’s disease

eLife ◽

10.7554/elife.32340 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 14

Author(s):

Antoine Guérin ◽

Gaspard Kerner ◽

Nico Marr ◽

Janet G Markle ◽

Florence Fenollar ◽

...

Keyword(s):

Autosomal Dominant ◽

Purifying Selection ◽

Tropheryma Whipplei ◽

Dominant Negative ◽

Incomplete Penetrance ◽

Whipple’S Disease ◽

Loss Of Function ◽

Whipple's Disease ◽

Age Dependent ◽

Chronic Carriage

Most humans are exposed to Tropheryma whipplei (Tw). Whipple’s disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.

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Detection of a new deleterious SGCE gene variant in Moroccan family with inherited Myoclonic-dystonia

10.22541/au.163254136.66611445/v1 ◽

2021 ◽

Author(s):

chbel faiza ◽

charoute hicham ◽

Boulouiz redouane ◽

Hamdaoui Hasna ◽

Mossafa Houssein ◽

...

Keyword(s):

Autosomal Dominant ◽

Dominant Mode ◽

Incomplete Penetrance ◽

Gene Variant ◽

Pathogenic Variants ◽

Modeling Analysis ◽

Moroccan Family ◽

Myoclonus Dystonia ◽

Maternal Imprinting ◽

Mode Of Inheritance

Myoclonus-Dystonia is a neuropsychiatric disorder with autosomal dominant mode of inheritance with variable severity and incomplete penetrance. Pathogenic variants in SGCE are the most frequent genetic cause of M-D with maternal imprinting. Herein we report a new deleterious variant based on protein modeling analysis (c.662G> T) inherited in moroccan family.

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Faculty Opinions recommendation of Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1011934.186378 ◽

2003 ◽

Author(s):

Andrew Wilkie

Keyword(s):

Autosomal Dominant ◽

Kallmann Syndrome ◽

Loss Of Function

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ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants

Neurogenetics ◽

10.1007/s10048-021-00655-4 ◽

2021 ◽

Author(s):

Katja Kloth ◽

Bernarda Lozic ◽

Julia Tagoe ◽

Mariëtte J. V. Hoffer ◽

Amelie Van der Ven ◽

...

Keyword(s):

Autosomal Recessive ◽

Neuronal Development ◽

Autosomal Dominant ◽

Tissue Expression ◽

Autism Spectrum ◽

Loss Of Function ◽

Ankyrin G ◽

Phenotypic Spectrum ◽

And Function ◽

Neurodevelopmental Phenotype

AbstractANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.

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Functional IRF3 deficiency in a patient with herpes simplex encephalitis

Journal of Experimental Medicine ◽

10.1084/jem.20142274 ◽

2015 ◽

Vol 212 (9) ◽

pp. 1371-1379 ◽

Cited By ~ 98

Author(s):

Line Lykke Andersen ◽

Nanna Mørk ◽

Line S. Reinert ◽

Emil Kofod-Olsen ◽

Ryo Narita ◽

...

Keyword(s):

Herpes Simplex ◽

Autosomal Dominant ◽

Viral Infections ◽

Herpes Simplex Encephalitis ◽

Type I ◽

Toll Like Receptor ◽

Loss Of Function ◽

Impaired Ability ◽

Increased Susceptibility ◽

Hsv 1

Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3–TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans.

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