European Journal of Human Genetics : EJHG (journal) (2024)

Laura M Watts, Marta Bertoli, Tania Attie-Bitach, Natalie Roux, Antonio Rausell, Cate R Paschal, Jessica L Zambonin, Cynthia J Curry, Blanche Martin, Rebecca S Tooze, Lara Hawkes, Usha Kini, Stephen R F Twigg, Andrew O M Wilkie

Carpenter syndrome (CRPTS) is a rare autosomal recessive condition caused by biallelic variants in genes that encode negative regulators of hedgehog signalling (RAB23 [CRPT1] or, more rarely, MEGF8 [CRPT2]), and is characterised by craniosynostosis, polysyndactyly, and other congenital abnormalities. We describe a further six families comprising eight individuals with MEGF8-associated CRPT2, increasing the total number of reported cases to fifteen, and refine the phenotype of CRPT2 compared to CRPT1. The core features of craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2...

May 17, 2024: European Journal of Human Genetics: EJHG

Oliver Feeney

No abstract text is available yet for this article.

May 16, 2024: European Journal of Human Genetics: EJHG

Fatoumata Faye, Claudia Crocione, Roberta Anido de Peña, Simona Bellagambi, Luciana Escati Peñaloza, Amy Hunter, Lene Jensen, Cor Oosterwijk, Eva Schoeters, Daniel de Vicente, Laurence Faivre, Michael Wilbur, Yann Le Cam, Jessie Dubief

Timely diagnosis is one of the most serious challenges faced by people living with a rare disease (PLWRD), and this study estimates that in Europe, the average total diagnosis time (TDT) is close to 5 years. We investigated the duration of the TDT for PLWRD in Europe, the difficulties associated with their diagnosis odyssey and the main determinants of diagnosis delays for all rare diseases (RD). We conducted a survey of PLWRD and their families using Rare Barometer, the survey initiative of EURORDIS-Rare Diseases Europe...

May 16, 2024: European Journal of Human Genetics: EJHG

Annabelle Chaussenot, Xavier Ayrignac, Nicolas Chatron, Terry Granchon-Riolzir, Pierre Labauge, Elisabeth Tournier-Lasserve, Florence Riant

Loss-of-function variants in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations. However, genomic DNA sequencing combined with large rearrangement screening fails to detect a pathogenic variant in 5% of the patients. We report a family with two affected members harboring multiple CCM lesions, one with severe hemorrhages and one asymptomatic. No causative variant was detected using DNA sequencing of the three CCM genes, CNV detection analysis, and RNA sequencing...

May 16, 2024: European Journal of Human Genetics: EJHG

Sophia Hammer-Hansen, Ulrik Stoltze, Emil Bartels, Thomas van Overeem Hansen, Anna Byrjalsen, Anne Tybjærg-Hansen, Klaus Juul, Kjeld Schmiegelow, Jacob Tfelt, Henning Bundgaard, Karin Wadt, Birgitte Rode Diness

The care for patients with serious conditions is increasingly guided by genomic medicine, and genomic medicine may equally transform care for healthy individual if genomic population screening is implemented. This study examines the medical impact of opportunistic genomic screening (OGS) in a cohort of patients undergoing comprehensive genomic germline DNA testing for childhood cancer, including the impact on their relatives. Medical actionability and uptake after cascade testing in the period following disclosure of OGS results was quantified...

May 13, 2024: European Journal of Human Genetics: EJHG

Xiaona Lu, Kim Ng, Filippo Pinto E Vairo, James Collins, Ronald Cohn, Kacie Riley, Katherine Agre, Ralitza Gavrilova, Eric W Klee, Jill A Rosenfeld, Yong-Hui Jiang

Numerous large scale genomic studies have uncovered rare but recurrent pathogenetic variants in a significant number of genes encoding epigenetic machinery in cases with neurodevelopmental disorders (NDD) especially autism spectrum disorder (ASD). These findings provide strong support for the functional importance of epigenetic regulators in neurodevelopment. After the clinical genomics evaluation of the patients using exome sequencing, we have identified, three novel protein-truncating variants (PTVs) in the MSL2 gene (OMIM: 614802) which encodes a chromatin modifying enzyme...

May 3, 2024: European Journal of Human Genetics: EJHG

Swati Singh, Sheela Nampoothiri, Dhanya Lakshmi Narayanan, Chakshu Chaudhry, Sandesh Salvankar, Katta M Girisha

Orofaciodigital syndrome is a distinctive subtype of skeletal ciliopathies. Disease-causing variants in the genes encoding the CPLANE complex result in a wide variety of skeletal dysplasia with disturbed ciliary functions. The phenotypic spectrum includes orofaciodigital syndrome and short rib polydactyly syndrome. FUZ, as a part of the CPLANE complex, is involved in intraflagellar vesicular trafficking within primary cilia. Previously, the variants, c.98_111+9del and c.851G>T in FUZ were identified in two individuals with a skeletal ciliopathy, manifesting digital anomalies (polydactyly, syndactyly), orofacial cleft, short ribs and cardiac defects...

May 3, 2024: European Journal of Human Genetics: EJHG

Magriet van Niekerk, Shahida Moosa, Ronald van Toorn, Regan Solomons

Next generation sequencing (NGS)-based tests have become routine first-line investigative modalities in paediatric neurology clinics in many high-income countries (HICs). Studies from these countries show that these tests are both cost-effective and reliable in diagnosing many complex childhood neurological diseases. However, NGS-based testing in low-and middle-income countries (LMICs) is limited due to affordability constraints. The primary objective of this study was to evaluate the diagnostic yield and impact of targeted gene panel sequencing in a selected paediatric cohort attending a tertiary paediatric neurology clinic in the Western Cape Province of South Africa...

May 3, 2024: European Journal of Human Genetics: EJHG

Ilaria Pettenuzzo, Sara Carli, Ana Sánchez-Cuesta, Federica Isidori, Francesca Montanari, Mina Grippa, Giulia Lanzoni, Irene Ambrosetti, Veronica Di Pisa, Duccio Maria Cordelli, Maria Cristina Mondardini, Tommaso Pippucci, Luca Ragni, Giovanna Cenacchi, Roberta Costa, Mario Lima, Maria Antonietta Capristo, Concetta Valentina Tropeano, Leonardo Caporali, Valerio Carelli, Elena Brunelli, Monica Maffei, Hodman Ahmed Sheikhmaye, Anna Fetta, Gloria Brea-Calvo, Caterina Garone

COQ7 pathogenetic variants cause primary CoQ10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation...

May 3, 2024: European Journal of Human Genetics: EJHG

Dana E Layo-Carris, Emily E Lubin, Annabel K Sangree, Kelly J Clark, Emily L Durham, Elizabeth M Gonzalez, Sarina Smith, Rajesh Angireddy, Xiao Min Wang, Erin Weiss, Roberto Mendoza-Londono, Lucie Dupuis, Nadirah Damseh, Danita Velasco, Irene Valenzuela, Marta Codina-Solà, Catherine Ziats, Jaclyn Have, Katie Clarkson, Dora Steel, Manju Kurian, Katy Barwick, Diana Carrasco, Aditi I Dagli, M J M Nowaczyk, Miroslava Hančárová, Šárka Bendová, Darina Prchalova, Zdeněk Sedláček, Alica Baxová, Catherine Bearce Nowak, Jessica Douglas, Wendy K Chung, Nicola Longo, Konrad Platzer, Chiara Klöckner, Luisa Averdunk, Dagmar Wieczorek, Ilona Krey, Christiane Zweier, Andre Reis, Tugce Balci, Marleen Simon, Hester Y Kroes, Antje Wiesener, Georgia Vasileiou, Nikolaos M Marinakis, Danai Veltra, Christalena Sofocleous, Konstantina Kosma, Joanne Traeger Synodinos, Konstantinos A Voudris, Marie-Laure Vuillaume, Paul Gueguen, Nicolas Derive, Estelle Colin, Clarisse Battault, Billie Au, Martin Delatycki, Mathew Wallis, Lyndon Gallacher, Fatma Majdoub, Noor Smal, Sarah Weckhuysen, An-Sofie Schoonjans, R Frank Kooy, Marije Meuwissen, Benjamin T Cocanougher, Kathryn Taylor, Carolyn E Pizoli, Marie T McDonald, Philip James, Elizabeth R Roeder, Rebecca Littlejohn, Nicholas A Borja, Willa Thorson, Kristine King, Radka Stoeva, Manon Suerink, Esther Nibbeling, Stephanie Baskin, Gwenaël L E Guyader, Julie Kaplan, Candace Muss, Deanna Alexis Carere, Elizabeth J K Bhoj, Laura M Bryant

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals...

April 27, 2024: European Journal of Human Genetics: EJHG

Tamar Nov-Klaiman, Hilary Bowman-Smart, Ruth Horn

Foetal-related severity is a key concept in policy and legislation relating to access to both reproductive technologies and selective abortions in many countries around the world, but not in Germany. This study sheds light on how 'severity' in the context of prenatal testing is understood and negotiated within the particular socio-cultural and legal context of Germany, where 'severity' relating to foetal clinical findings neither counts as a justification to implement population prenatal screening programs, nor as a legal ground to terminate pregnancy...

April 27, 2024: European Journal of Human Genetics: EJHG

Venugopalan Y Vishnu, Richard J L F Lemmers, Alisha Reyaz, Rinkle Mishra, Tanveer Ahmad, Patrick J van der Vliet, Marcelina M Kretkiewicz, William L Macken, Stephanie Efthymiou, Natalia Dominik, Jasper M Morrow, Rohit Bhatia, Lindsay A Wilson, Henry Houlden, Michael G Hanna, Enrico Bugiardini, Silvère M van der Maarel, M V Padma Srivastava

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of hereditary myopathy. Sixty per cent of the world's population lives in Asia, so a significant percentage of the world's FSHD participants is expected to live there. To date, most FSHD studies have involved individuals of European descent, yet small-scale studies of East-Asian populations suggest that the likelihood of developing FSHD may vary. Here, we present the first genetically confirmed FSHD cohort of Indian ancestry, which suggests a pathogenic FSHD1 allele size distribution intermediate between European and North-East Asian populations and more asymptomatic carriers of 4 unit and 5 unit FSHD1 alleles than observed in European populations...

April 25, 2024: European Journal of Human Genetics: EJHG

Maria A Andrianova, Vladimir B Seplyarskiy, Mariona Terradas, Ana Beatriz Sánchez-Heras, Pilar Mur, José Luis Soto, Gemma Aiza, Emma Borràs, Fyodor A Kondrashov, Alexey S Kondrashov, Georgii A Bazykin, Laura Valle

Constitutional heterozygous pathogenic variants in the exonuclease domain of POLE and POLD1, which affect the proofreading activity of thecorresponding polymerases, cause a cancer predisposition syndrome characterized by increased risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and other tumor types. The generally accepted explanation for the connection between the disruption of the proofreading activity of polymerases epsilon and delta and cancer development is through an increase in the somatic mutation rate...

April 24, 2024: European Journal of Human Genetics: EJHG

Cassandra Muller, Lyndon Gallacher, Louise Keogh, Aideen McInerney-Leo, Tiffany Boughtwood, Penny Gleeson, Kristine Barlow-Stewart, Martin B Delatycki, Ingrid Winship, Kristen J Nowak, Margaret Otlowski, Paul Lacaze, Jane Tiller

Genetic testing can provide valuable information to mitigate personal disease risk, but the use of genetic results in life insurance underwriting is known to deter many consumers from pursuing genetic testing. In 2019, following Australian Federal Parliamentary Inquiry recommendations, the Financial Services Council (FSC) introduced an industry-led partial moratorium, prohibiting life insurance companies from using genetic test results for policies up to $AUD500,000. We used semi-structured interviews to explore genetic test consumers' experiences and views about the FSC moratorium and the use of genetic results by life insurers...

April 19, 2024: European Journal of Human Genetics: EJHG

Álvaro Mendes, Ainsley J Newson

No abstract text is available yet for this article.

April 16, 2024: European Journal of Human Genetics: EJHG

Yunlu Zhu, Yun Bai, Wannian Yan, Ming Li, Fei Wu, Mingyuan Xu, Nanhui Wu, HongSong Ge, Yeqiang Liu

Acrokeratoelastoidosis (AKE) is a rare autosomal dominant hereditary skin disease characterized by small, round-oval, flat-topped keratotic papules on the palms, soles and dorsal aspect of hands or feet. The causative gene for AKE remains unidentified. This study aims to identify the causative gene of AKE and explore the underlying biological mechanisms. A large, three-generation Chinese family exhibiting classic AKE symptoms was identified. A genome-wide linkage analysis and whole-exome sequencing were employed to determine the causative gene...

April 16, 2024: European Journal of Human Genetics: EJHG

Madeline Pearson, Ruth McGowan, Philip Greene, Wayne Lam, Zofia Miedzybrodzka, Jonathan Berg

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy...

April 16, 2024: European Journal of Human Genetics: EJHG

Ruth Horn, Jennifer Merchant

No abstract text is available yet for this article.

April 16, 2024: European Journal of Human Genetics: EJHG

Niels Vos, Lotte Kleinendorst, Liselot van der Laan, Jorrit van Uhm, Philip R Jansen, Agnies M van Eeghen, Saskia M Maas, Marcel M A M Mannens, Mieke M van Haelst

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial 'mirror phenotype' with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the 'typical' 16p11.2 BP4-BP5 (29.6-30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11...

April 11, 2024: European Journal of Human Genetics: EJHG

Andrew Fleming, Miranda Galey, Lizi Briggs, Matthew Edwards, Claire Hogg, Shibu John, Sam Wilkinson, Ellie Quinn, Ranjit Rai, Tom Burgoyne, Andy Rogers, Mitali P Patel, Paul Griffin, Steven Muller, Siobhan B Carr, Michael R Loebinger, Jane S Lucas, Anand Shah, Ricardo Jose, Hannah M Mitchison, Amelia Shoemark, Danny E Miller, Deborah J Morris-Rosendahl

Primary ciliary dyskinesia (PCD), a disorder of the motile cilia, is now recognised as an underdiagnosed cause of bronchiectasis. Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including HYDIN. HYDIN-related PCD is underdiagnosed due to the presence of a pseudogene, HYDIN2, with 98% sequence hom*ology to HYDIN. This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include HYDIN...

April 11, 2024: European Journal of Human Genetics: EJHG

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