| 1. |
- Horikoshi, Momoko, et al.
(författare)
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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:1
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Tidskriftsartikel (refereegranskat)abstract
- Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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| 2. |
- Chen, Yin Huai, et al.
(författare)
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Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome
- 2020
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 217:3
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Tidskriftsartikel (refereegranskat)abstract
- The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.
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| 3. |
- Palmer, Elizabeth E., et al.
(författare)
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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
- 2023
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Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; 28:2, s. 668-697
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Tidskriftsartikel (refereegranskat)abstract
- Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
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| 4. |
- Magliyah, Moustafa S., et al.
(författare)
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Leprel1-related Giant Retinal Tear Detachments Mimic the Phenotype of Ocular Stickler Syndrome
- 2023
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Ingår i: Retina. - 0275-004X. ; 43:3, s. 498-505
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:To describe the features of retinal detachments and high myopia in patients with novel pathogenic variants in LEPREL1 and report a possible association with nephropathy.Methods:Retrospective study of 10 children with biallelic LEPREL1 pathogenic variants. Data included ophthalmic features, surgical interventions, and genetic and laboratory findings.Results:10 patients (8 females) from three families with homozygous (2) or compound heterozygous (1) variants in LEPREL1 were included. At presentation, mean age was 9.9 ± 2.6 years. Mean axial length was 28.9 ± 1.9 mm and mean refraction was -13.9 ± 2.8 diopters. Bilateral posterior subcapsular cataracts were present in eight patients (80%), with lens subluxation in five eyes of three patients (30%). Rhegmatogenous retinal detachments (RRD), associated with giant retinal tears (GRT), developed in seven eyes of five patients (50%) at a mean age of 14.14 ± 5.9 years. Six were successfully reattached with mean Snellen best-corrected visual acuity improving from 20/120 preoperatively to 20/60 at last follow-up. Urinalysis in nine patients revealed microhematuria and/or mild proteinuria in six patients (67%).Conclusion:LEPREL1-related high myopia confers a high risk of early-onset GRT-related RRD. The ocular phenotype may be confused with that of ocular Stickler syndrome if genetic testing is not performed. Further investigations into a potential association with renal dysfunction are warranted.
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| 5. |
- Magliyah, Moustafa S., et al.
(författare)
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Rhegmatogenous Retinal Detachment in Nonsyndromic High Myopia Associated with Recessive Mutations in LRPAP1
- 2020
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Ingår i: Ophthalmology Retina. - : Elsevier BV. - 2468-6530. ; 4:1, s. 77-83
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Konferensbidrag (refereegranskat)abstract
- Purpose: To describe a new form of childhood-onset rhegmatogenous retinal detachment (RRD) in autosomal recessive high myopia associated with mutations in LRPAP1. Design: Retrospective cohort study. Participants: A total of 12 children (24 eyes) with recessive LRPAP1 mutations and associated high myopia. Methods: Serial ophthalmological examination and retinal imaging during 4.6±1.9 (mean ± standard deviation) years. Retinal interventions included prophylactic laser and surgical retinal repair. Main Outcome Measures: Incidence and recurrence rate of RRD and retinal break formation. Association between LRPAP1 genotypes and RRD characteristics. Results: Some 42% of children (5 children [6 eyes]) developed RRD at the age of 10.43±0.97 years. Four of the children who developed RRD were male (80%), and 1 was female (20%). Visual acuity was significantly reduced in eyes with RRD at presentation and at the most recent visit compared with eyes with no RRD (P < 0.001 for both). Two eyes had inoperable RRD. Four eyes for which primary retinal repair was done had redetachment (100% of operated eyes) due to variable degrees of proliferative vitreoretinopathy (PVR). Reattachment after surgical repair, which was maintained at least during 6 months of follow-up, was achieved in 3 eyes (75%), with final visual acuities of 20/300 in 2 eyes and 20/400 in 1 eye. Conclusions: This is the first description of a nonsyndromic, high myopia-related, recessive RRD without any signs of vitreoretinal degeneration. Recessive LRPAP1 gene mutations confer a high risk of childhood-onset RRD and PVR. Proliferative vitreoretinopathy in turn increases the risk of recurrent RRD and may lead to blindness. Recognizing the LRPAP1-related high myopia phenotype is important, and early childhood examination with additional close follow-up and prophylactic retinal laser should be considered.
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| 6. |
- Badawi, Abdulrahman, et al.
(författare)
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Cone dystrophy associated with autoimmune polyglandular syndrome type 1
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- To report the association of autoimmune polyglandular syndrome type 1 (APS1) with cone dystrophy in a large Saudi family. This is a Retrospective chart review and prospective genetic testing and ophthalmic examination of a large multiplex consanguineous family. Genetic testing was performed on 14 family members, seven of whom had detailed ophthalmic examinations. Medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG), and Whole Exome Sequencing (WES) results were analyzed. Three family members were homozygous for c.205_208dupCAGG;p.(Asp70Alafs*148) in AIRE and homozygous for c.481-1G>A in PDE6C. One additional family member was homozygous for only the AIRE variant and another additional family member was homozygous for only the PDE6C variant. All patients with homozygosity for the PDE6C variant had cone dystrophy, and all patients with homozygosity for the AIRE variant had APS1. In addition, two of the family members who were homozygous for the PDE6C and AIRE variants had reduced rod function on ERG. We report the co-inheritance for APS1 and PDE6C-related cone dystrophy, an unusual example of two seemingly independent recessive conditions coinciding within a family. Dual molecular diagnosis must be taken into account by ophthalmologists facing unusual constellations of findings, especially in consanguineous families.
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| 7. |
- Shankar, Suma P., et al.
(författare)
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A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder
- 2022
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 24:7, s. 1567-1582
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). Methods: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate–ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. Results: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate–ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. Conclusion: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
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| 8. |
- Sukalo, Maja, et al.
(författare)
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Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum
- 2014
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 35:5, s. 521-531
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Tidskriftsartikel (refereegranskat)abstract
- Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n=29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.
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