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EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis
Adamo et  al. describe a cutis laxa syndrome caused by bi-allelic loss-of-function variants in EMILIN1 characterized by arterial tortuosity, aneurysm formation, and osteopenia. They provide a model in which EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vas cular tissue homeostasis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 8, 2022 Category: Genetics & Stem Cells Authors: Christin S. Adamo, Aude Beyens, Alvise Schiavinato, Douglas R. Keene, Sara F. Tufa, Matthias M örgelin, Jürgen Brinckmann, Takako Sasaki, Anja Niehoff, Maren Dreiner, Lore Pottie, Laura Muiño-Mosquera, Elif Yilmaz Gulec, Alper Gezdirici, Paola Braghett Tags: Article Source Type: research

Systematic comparison of family history and polygenic risk across 24 common diseases
Leveraging family relationships, nationwide registries, and genome-wide genotyping, Mars et  al. systematically compared two measures of inherited disease risk across 24 diseases: family history and polygenic risk scores. The measures provided complementary information for risk assessment, demonstrating opportunities for a more comprehensive way of assessing inherited risk in clinical car e. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 7, 2022 Category: Genetics & Stem Cells Authors: Nina Mars, Joni V. Lindbohm, Pietro della Briotta Parolo, Elisabeth Wid én, Jaakko Kaprio, Aarno Palotie, FinnGen, Samuli Ripatti Tags: Article Source Type: research

The recurrent de novo c.2011C > T missense variant in MTSS2 causes syndromic intellectual disability
(The American Journal of Human Genetics 109, 1923 –1931; October 6, 2022) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 3, 2022 Category: Genetics & Stem Cells Authors: Yan Huang, Gabrielle Lemire, Lauren C. Briere, Fang Liu, Marja W. Wessels, Xueqi Wang, Matthew Osmond, Oguz Kanca, Shenzhao Lu, Frances A. High, Melissa A. Walker, Lance H. Rodan, Undiagnosed Diseases Network, Care4Rare Canada Consortium, Michael F. Wangl Tags: Correction Source Type: research

Response to Eura et  al.
To the Editor: We appreciate Eura et  al.1 for their interest in our recently published work. We read their letter, which demonstrated none of 159 Japanese individuals with ophthalmopharyngeal myopathy (OPDM) had abnormal CGG repeat expansion in the 5′ untranslated region (5′ UTR) of RILPL1 detected by RP-PCR, with great interest. The repeat sizes of all alleles detected by AL-PCR were within the range observed in unaffected controls. They concluded that the CGG repeat expansion in RILPL1 was rare in the Japanese cohort of individuals with OPDM. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 3, 2022 Category: Genetics & Stem Cells Authors: Jiaxi Yu, Jingli Shan, Meng Yu, Li Di, Zhiying Xie, Wei Zhang, He Lv, LingChao Meng, Yiming Zheng, Yawen Zhao, Qiang Gang, Xueyu Guo, Yang Wang, Jianying Xi, Wenhua Zhu, Yuwei Da, Daojun Hong, Yun Yuan, Chuanzhu Yan, Zhaoxia Wang, Jianwen Deng Tags: Letter to the Editor Source Type: research

RILPL1-related OPDM is absent in a Japanese cohort
To the Editor: We have read with great interest the recent article “The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4” by Yu et al.1 The authors identified the CGG repeat expansions in RILPL1 (MIM: 614092) in 11 unrelated individuals with oculopharyngodistal myopathy (OPDM) in China, which has become the fourth gene with a variant causative of OPDM after LRP12 (MIM: 618299), GIPC1 (MIM: 605072), and NOTCH2NLC (MIM: 618025).1,2,3,4,5 More recently, another group from China also reported on individuals with CGG expansion in RILPL1 in two families with OPDM. (Source: The American J...
Source: The American Journal of Human Genetics - November 3, 2022 Category: Genetics & Stem Cells Authors: Nobuyuki Eura, Aritoshi Iida, Masashi Ogasawara, Shinichiro Hayashi, Satoru Noguchi, Ichizo Nishino Tags: Letter to the Editor Source Type: research

Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation
Sharing genomic variant interpretations across laboratories promotes consistency. The Shariant platform was developed to enable ongoing sharing of variant interpretations and associated evidence, resolution of inter-laboratory discrepancies, and streamlined submission of variant assertions to ClinVar. This approach has improved concordance and enabled opportunities for standardization of practices between Australian laboratories. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 3, 2022 Category: Genetics & Stem Cells Authors: Emma Tudini, James Andrews, David M. Lawrence, Sarah L. King-Smith, Naomi Baker, Leanne Baxter, John Beilby, Bruce Bennetts, Victoria Beshay, Michael Black, Tiffany F. Boughtwood, Kristian Brion, Pak Leng Cheong, Michael Christie, John Christodoulou, Beli Tags: Technology Review Source Type: research

Care4Rare Canada: Outcomes from a decade of network science for rare disease gene discovery
After a decade of collaborative network science in Canada and three eras of RD gene discovery, the Care4Rare Canada Consortium recognized it was time to reflect on the lessons learned from our successes to best meet the challenges of RD diagnosis and discovery in the decade to come. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 3, 2022 Category: Genetics & Stem Cells Authors: Kym M. Boycott, Taila Hartley, Kristin D. Kernohan, David A. Dyment, Heather Howley, A. Micheil Innes, Francois P. Bernier, Michael Brudno, Care4Rare Canada Consortium Tags: Perspective Source Type: research

This month in The Journal
Boycott et  al., p. 1947 (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 3, 2022 Category: Genetics & Stem Cells Authors: Kylee L. Spencer, Sara B. Cullinan Tags: Editors' Corner Source Type: research

A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
Founder effects for childhood disorders occur in recessive conditions. We infer an ∼800-year-old founder for an autosomal dominant allele (SCN1B, c.363C>G) causing childhood-onset epilepsy in 14 families. Also present in 74  UK Biobank individuals, it may have escaped negative selection because of a mild phenotype and incomplete penetrance. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 25, 2022 Category: Genetics & Stem Cells Authors: Bronwyn E. Grinton, Erandee Robertson, Liam G. Fearnley, Ingrid E. Scheffer, Anthony G. Marson, Terence J. O ’Brien, W. Owen Pickrell, Mark I. Rees, Sanjay M. Sisodiya, David J. Balding, Mark F. Bennett, Melanie Bahlo, Samuel F. Berkovic, Karen L. Olive Tags: Report Source Type: research

Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder
We describe bi-allelic variants in CAMSAP1, which encodes a molecule crucially important for minus-end microtubule stabilization, as a cause of a clinically recognizable, syndromic neuronal migration disorder with similarities to the “tubulinopathies.” Camsap1−/− mice displayed increased perinatal mortality, and proband-derived neural cell rosette lineages showed decreased cell proliferation and differentiation. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 24, 2022 Category: Genetics & Stem Cells Authors: Reham Khalaf-Nazzal, James Fasham, Katherine A. Inskeep, Lauren E. Blizzard, Joseph S. Leslie, Matthew N. Wakeling, Nishanka Ubeyratna, Tadahiro Mitani, Jennifer L. Griffith, Wisam Baker, Fida ’ Al-Hijawi, Karen C. Keough, Alper Gezdirici, Loren Pena, C Tags: Report Source Type: research

Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models
The authors present functional characterization of a CRISPR-engineered allelic series of deletions altering MEF2C and the 3D regulatory architecture encompassing the 5q14.3 microdeletion syndrome region. They find that direct deletion of MEF2C and some, but not all, 3D regulatory interactions result in shared transcriptional and electrophysiological deficits in early neurodevelopment. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 24, 2022 Category: Genetics & Stem Cells Authors: Kiana Mohajeri, Rachita Yadav, Eva D'haene, Philip M. Boone, Serkan Erdin, Dadi Gao, Mariana Moyses-Oliveira, Riya Bhavsar, Benjamin B. Currall, Kathryn O'Keefe, Nicholas D. Burt, Chelsea Lowther, Diane Lucente, Monica Salani, Mathew Larson, Claire Redin, Tags: Article Source Type: research

Liability-scale heritability estimation for biobank studies of low-prevalence disease
Estimating the heritability of low-prevalence diseases in biobanks can lead to inconsistent and unrealistic results because of high estimator variance. Here, we propose a simple alternative that increases the heritability estimation accuracy for low-prevalence traits that is also suitable for ascertained samples. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 19, 2022 Category: Genetics & Stem Cells Authors: Sven E. Ojavee, Zoltan Kutalik, Matthew R. Robinson Tags: Article Source Type: research

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts
The prevalence of pathogenic variants in common MODY-associated genes are ∼1:1,500 in the population. The penetrance of pathogenic HNF1A and HNF4A variants, but not of GCK variants, is substantially lower when found incidentally. Our findings are important for incidental reporting of pathogenic variants in MODY and other monogenic disorders. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 17, 2022 Category: Genetics & Stem Cells Authors: Uyenlinh L Mirshahi, Kevin Colclough, Caroline F Wright, Andrew R Wood, Robin N Beaumont, Jessica Tyrrell, Thomas W Laver, Richard Stahl, Alicia Golden, Jessica M Goehringer, Geisinger-Regeneron DiscovEHR Collaboration, Timothy F Frayling, Andrew T Hatter Tags: Article Source Type: research

Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy
This study supports that this condition is a retinal enhanceropathy. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 14, 2022 Category: Genetics & Stem Cells Authors: Stijn Van de Sompele, Kent W. Small, Munevver Burcu Cicekdal, V íctor López Soriano, Eva D’haene, Fadi S. Shaya, Steven Agemy, Thijs Van der Snickt, Alfredo Dueñas Rey, Toon Rosseel, Mattias Van Heetvelde, Sarah Vergult, Irina Balikova, Arthur A. Ber Tags: Article Source Type: research

The construction of cross-population polygenic risk scores using transfer learning
Existing polygenic risk score (PRS) models have limited transferability across ancestry groups. We propose a PRS method, TL-PRS, using transfer learning techniques to fine-tune the baseline PRS model to the target ancestry. The simulation and application results show that our approach increases the transferability of PRSs across ancestries. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 13, 2022 Category: Genetics & Stem Cells Authors: Zhangchen Zhao, Lars G. Fritsche, Jennifer A. Smith, Bhramar Mukherjee, Seunggeun Lee Tags: Article Source Type: research