Novel RPL13 variants and evidence for incomplete penetrance in a human ribosomopathy with spondyloepimetaphyseal dysplasia

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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Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies

Therapeutic Advances in Ophthalmology ◽

10.1177/2515841421997191 ◽

2021 ◽

Vol 13 ◽

pp. 251584142199719

Author(s):

Simranjeet Singh Grewal ◽

Joseph J. Smith ◽

Amanda-Jayne F. Carr

Keyword(s):

Pigment Epithelium ◽

Retinal Pigment ◽

Induced Pluripotent Stem Cell ◽

Underlying Disease ◽

Incomplete Penetrance ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies ◽

High Acuity ◽

Induced Pluripotent

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum of disorders is caused by mutations in bestrophin1 ( BEST1), a protein thought to act as a Ca2+-activated Cl- channel in the retinal pigment epithelium (RPE) of the eye. Although bestrophinopathies are rare, over 250 individual pathological mutations have been identified in the BEST1 gene, with many reported to have various clinical expressivity and incomplete penetrance. With no current clinical treatments available for patients with bestrophinopathies, understanding the role of BEST1 in cells and the pathological pathways underlying disease has become a priority. Induced pluripotent stem cell (iPSC) technology is helping to uncover disease mechanisms and develop treatments for RPE diseases, like bestrophinopathies. Here, we provide a comprehensive review of the pathophysiology of bestrophinopathies and highlight how patient-derived iPSC-RPE are being used to test new genomic therapies in vitro.

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DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome

Clinical Epigenetics ◽

10.1186/s13148-020-00990-7 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

L. C. Schenkel ◽

E. Aref-Eshghi ◽

K. Rooney ◽

J. Kerkhof ◽

M. A. Levy ◽

...

Keyword(s):

Dna Methylation ◽

Critical Region ◽

Deletion Syndrome ◽

Genetic Defects ◽

Chromosome 22 ◽

Incomplete Penetrance ◽

Variable Size ◽

Variable Expressivity ◽

Genome Wide ◽

22Q13.3 Deletion Syndrome

Abstract Background Phelan-McDermid syndrome is characterized by a range of neurodevelopmental phenotypes with incomplete penetrance and variable expressivity. It is caused by a variable size and breakpoint microdeletions in the distal long arm of chromosome 22, referred to as 22q13.3 deletion syndrome, including the SHANK3 gene. Genetic defects in a growing number of neurodevelopmental genes have been shown to cause genome-wide disruptions in epigenomic profiles referred to as epi-signatures in affected individuals. Results In this study we assessed genome-wide DNA methylation profiles in a cohort of 22 individuals with Phelan-McDermid syndrome, including 11 individuals with large (2 to 5.8 Mb) 22q13.3 deletions, 10 with small deletions (< 1 Mb) or intragenic variants in SHANK3 and one mosaic case. We describe a novel genome-wide DNA methylation epi-signature in a subset of individuals with Phelan-McDermid syndrome. Conclusion We identified the critical region including the BRD1 gene as responsible for the Phelan-McDermid syndrome epi-signature. Metabolomic profiles of individuals with the DNA methylation epi-signature showed significantly different metabolomic profiles indicating evidence of two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.

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Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum

Genes ◽

10.3390/genes12081128 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1128

Author(s):

Marilena Nakaguma ◽

Nathalia Garcia Bianchi Pereira Ferreira ◽

Anna Flavia Figueredo Benedetti ◽

Mariana Cotarelli Madi ◽

Juliana Moreira Silva ◽

...

Keyword(s):

Growth Hormone ◽

Male Patient ◽

Missense Variant ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Incomplete Penetrance ◽

Growth Hormone Gene ◽

Posterior Lobe ◽

Allelic Variants ◽

Phenotypic Spectrum

We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

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fshr: a fish sex-determining locus shows variable incomplete penetrance across flathead grey mullet populations

iScience ◽

10.1016/j.isci.2020.101886 ◽

2021 ◽

Vol 24 (1) ◽

pp. 101886

Author(s):

Serena Ferraresso ◽

Luca Bargelloni ◽

Massimiliano Babbucci ◽

Rita Cannas ◽

Maria Cristina Follesa ◽

...

Keyword(s):

Incomplete Penetrance ◽

Grey Mullet

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Unusual phenotypes in patients with a pathogenic germline variant in DICER1

Familial Cancer ◽

10.1007/s10689-021-00271-z ◽

2021 ◽

Author(s):

Kateryna Venger ◽

Miriam Elbracht ◽

Julia Carlens ◽

Peter Deutz ◽

Felix Zeppernick ◽

...

Keyword(s):

Wilms Tumor ◽

Pleuropulmonary Blastoma ◽

Global Developmental Delay ◽

Facial Dysmorphism ◽

Compound Heterozygous ◽

Incomplete Penetrance ◽

Developmental Abnormalities ◽

Lung Cysts ◽

Developmental Features ◽

Skeletal Findings

AbstractPathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense DICER1 variants in the RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. Here, we report four families with germline DICER1 pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with DICER1 variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in ARID1B was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic DICER1 variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.

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