Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

Küry, Sébastien; Ebstein, Frédéric; Mollé, Alice; Besnard, Thomas; Lee, Ming-Kang; Vignard, Virginie; Héry, Tiphaine; Nizon, Mathilde; Mancini, Grazia M.S.; Giltay, Jacques C.; Cogné, Benjamin; McWalter, Kirsty; Deb, Wallid; Mor‐Shaked, Hagar; Li, Hong; Schnur, Rhonda E.; Wentzensen, Ingrid M.; Denommé‐Pichon, Anne‐Sophie; Fourgeux, Cynthia; Verheijen, Frans W.; Faurie, E.; Schot, Rachel; Stevens, Cathy A.; Smits, Daphne J.; Barr, Eileen; Sheffer, Ruth; Bernstein, Jonathan A.; Stimach, Chandler; Kovitch, Eliana; Shashi, Vandana; Schoch, Kelly; Smith, Whitney; Jaarsveld, Richard H. van; Hurst, Anna; Smith, Kirstin; Baugh, Evan H.; Bohm, Suzanne G.; Vyhnálková, Emílie; Ryba, Lukáš; Neira, Juanita; Bonneau, Dominique; Toutain, Annick; Rosenfeld, Jill A.; Audebert‐Bellanger, Séverine; Gilbert‐Dussardier, Brigitte; Odent, Sylvie; Laumonnier, Frédéric; Berger, Seth; Smith, Ann C. M.; Bourdeaut, Franck; Stern, Marc-Henri; Redon, Richard; Krüger, Elke; Margueron, Raphaël; Bézieau, Stéphane; Poschmann, Jérémie; Isidor, Bertrand

doi:10.1016/j.ajhg.2021.12.011

Cited by 15 publications

(24 citation statements)

References 38 publications

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“…A germline BAP1 nonsense pathogenic variant was identified in a family presenting with familial meningioma with rhabdoid features [7]; somatic testing of meningiomas with rhabdoid features should include BAP1 evaluation [7]. Additionally, a recent case series demonstrated a new, separate, neurodevelopmental phenotype with no tumor predisposition associated with rare heterozygous missense variants in BAP1 [8].…”

Section: Bap1 Tumor Predisposition Syndromementioning

confidence: 99%

Tumor predisposition: what's the skin got to do with it?

Stacy

Shinawi

Coughlin

2022

Current Opinion in Pediatrics

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Purpose of reviewRecognition of skin findings associated with tumor predisposition syndromes can prompt early evaluation and surveillance and improve management. Additionally, knowing when to test and when to defer performing genetic testing can streamline management. This article reviews tumor predisposition syndromes with recently characterized skin findings and disorders for which early recognition and counseling can impact the course of disease.Recent findingsCafé au lait macules (CALMs) are important in many tumor predisposition syndromes, and ‘atypical’ CALMs are associated with constitutional mismatch repair deficiency and Fanconi anemia. Melanoma predisposition syndromes caused by pathogenic variants in POT1 and BAP1 are more recently described, and both are associated with Spitzoid tumors. Somatic pathogenic variants can cause segmental nevoid basal cell carcinoma syndrome and a mosaic form of Peutz–Jeghers syndrome. Patients with PTEN hamartoma syndrome have increased risk for melanoma but this might not occur until adulthood.SummaryThe cutaneous manifestations of tumor predisposition syndromes can aid diagnosis. Early photoprotection is key to modifying a main risk factor for skin cancer in many of these syndromes. Implementing surveillance guidelines facilitates early detection of tumors.

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Section: Bap1 Tumor Predisposition Syndromementioning

confidence: 99%

Tumor predisposition: what's the skin got to do with it?

Stacy

Shinawi

Coughlin

2022

Current Opinion in Pediatrics

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“…Kury et al 5 identified 11 individuals with a distinct neurodevelopmental disorder and heterozygous de novo BAP1 missense variants (see Table 1 and Figure 1). Intriguingly, none of the 11 subjects developed tumors of any type, although their ages ranged from 2 to 16 years at The site of the variants does not appear predictive of the associated phenotype, as all but one of the identified KURIS variants are in the peptidase-ubiquitin hydrolase domain (residues 5-233), similar to various TPDS1-associated variants (see Table 1 and Figure 1).…”

Section: Kury-isidor Syndrome (Kuris)mentioning

confidence: 99%

Section: Bap1 Functionmentioning

confidence: 99%

“…KURIS patients exhibit features affecting multiple body systems, including the nervous, immune, digestive, and cardiovascular systems. Abnormalities in the head (10/11 subjects), neck, limbs (7/11), distal‐skeletal axis, eyes (5/10 subjects), ears (4/11 subjects), growth (9/11 subjects), heart (3/10 subjects), and musculoskeletal system (7/11 subjects) are observed 5 . Behavioral and neurological manifestations include mild seizures (6/11 subjects), global developmental delay (11/11 subjects; two with severe delay and one with mild delay), language and speech difficulty (11/11 subjects), negative psychiatric disturbances and aggression (3/10 subjects), attention deficits (3/10 subjects), and autism spectrum disorder (3/10 subjects) 5 .…”

Section: Bap1 Functionmentioning

confidence: 99%

“…However, some BAP1 germline heterozygous missense variants have also been associated with a second condition: a neurodevelopmental disorder called Kury‐Isidor syndrome (KURIS) (MIM: 619762), a rare syndromic form of intellectual disability and congenital developmental delay 5 . This syndrome was only recently described and the actual incidence and clinical implications for patients and family management are still far from being established.…”

Section: Introductionmentioning

confidence: 99%

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BRCA1‐associated protein 1: Tumor predisposition syndrome and Kury‐Isidor syndrome, from genotype–phenotype correlation to clinical management

West,

Chiappetta,

Mattingly

et al. 2024

Clinical Genetics

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The BAP1 tumor suppressor gene encodes a deubiquitinase enzyme involved in several cellular activities, including DNA repair and apoptosis. Germline pathogenic variants in BAP1 have been associated with heritable conditions including BAP1 tumor predisposition syndrome 1 (BAP1‐TPDS1) and a neurodevelopmental disorder known as Kury‐Isidor syndrome (KURIS). Both these conditions are caused by monoallelic, dominant alterations of BAP1 but have never been reported in the same subject or family, suggesting a mutually exclusive genotype–phenotype correlation. This distinction is extremely important considering the early onset and aggressive nature of the types of cancer reported in individuals with TPDS1. Genetic counseling in subjects with germline BAP1 variants is fundamental to predicting the effect of the variant and the expected phenotype, assessing the potential risk of developing cancer for the tested subject and the family members who may carry the same variant and providing the multidisciplinary clinical team with the proper information to establish precise surveillance and management protocols.

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Germline findings in cancer predisposing genes from a small cohort of chordoma patients

Raygada,

John,

Liu

et al. 2024

J Cancer Res Clin Oncol

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Introduction Chordoma is a rare slow-growing tumor that occurs along the length of the spinal axis and arises from primitive notochordal remnants (Stepanek et al., Am J Med Genet 75:335–336, 1998). Most chordomas are sporadic, but a small percentage of cases are due to hereditary cancer syndromes (HCS) such as tuberous sclerosis 1 and 2 (TSC1/2), or constitutional variants in the gene encoding brachyury T (TBXT) (Pillay et al., Nat Genet 44:1185–1187, 2012; Yang et al., Nat Genet 41:1176–1178, 2009). Purpose The genetic susceptibility of these tumors is not well understood; there are only a small number of studies that have performed germline genetic testing in this population. Methods We performed germline genetic in chordoma patients using genomic DNA extracted by blood or saliva. Conclusion We report here a chordoma cohort of 24 families with newly found germline genetic mutations in cancer predisposing genes. We discuss implications for genetic counseling, clinical management, and universal germline genetic testing for cancer patients with solid tumors.

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Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

Cited by 15 publications

References 38 publications

Tumor predisposition: what's the skin got to do with it?

Tumor predisposition: what's the skin got to do with it?

BRCA1‐associated protein 1: Tumor predisposition syndrome and Kury‐Isidor syndrome, from genotype–phenotype correlation to clinical management

Germline findings in cancer predisposing genes from a small cohort of chordoma patients

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