Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Akawi, Nadia; McRae, Jeremy F.; Ansari, Morad; Balasubramanian, Meena; Blyth, Moira; Brady, Angela; Clayton, Stephen; Cole, Trevor; Deshpande, Charu; Fitzgerald, Tomas; Foulds, Nicola; Francis, Richard; Gabriel, George C.; Gerety, Sebastian S.; Goodship, Judith A.; Hobson, Emma; Jones, Wendy D.; Joss, Shelagh; King, Dan; Klena, Nikolai; Kumar, Ajith; Lees, Melissa; Lelliott, Chris J; Lord, Jenny; McMullan, Dominic; O’Regan, Mary; Osio, Deborah; Piombo, Virginia; Prigmore, Elena; Rajan, Diana; Rosser, Elisabeth; Smith, Audrey; Swaminathan, Ganesh; Turnpenny, Peter D.; Whitworth, James W.; Wright, Caroline F.; Firth, Helen V.; Barrett, Jeffrey C.; Lo, Cecilia; FitzPatrick, David R.; Hurles, Matthew E.

doi:10.1038/ng.3410

Cited by 142 publications

(171 citation statements)

References 42 publications

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“…Institute as previously described 54,55 . Data is currently available on 4,295 triomes which were interrogated via a DDD complementary research proposal (CAP#120).…”

Section: Kmt2b Dystonia Meyer Et Al 2016mentioning

confidence: 99%

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Meyer¹,

Carss²,

Rankin³

et al. 2016

Nat Genet

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Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-

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“…Institute as previously described 54,55 . Data is currently available on 4,295 triomes which were interrogated via a DDD complementary research proposal (CAP#120).…”

Section: Kmt2b Dystonia Meyer Et Al 2016mentioning

confidence: 99%

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Meyer¹,

Carss²,

Rankin³

et al. 2016

Nat Genet

Self Cite

198

253

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“…Son hérédité est récessive, comme chez l'homme, et une pénétrance incomplète 5 a été observée dans le modèle CRISPR/Cas9. Dans ces modèles, le cil du noeud embryonnaire fonctionnait normalement [6]. Une étude phylogénique a montré que le gène MMP21 n'est pas fonctionnel dans le génome de tous les vertébrés.…”

Section: Le Gène Mmp21unclassified

“…ne souffraient d'autres signes que ceux liés à l'hétérotaxie, suggérant que les mutations du gène MMP21 n'altéraient pas d'autres mécanismes cellulaires que celui lié à la latéralisation. En plus de ces huit familles, un cas familial supplémentaire hispano-américain est rapporté dans l'article de Guimier et al [5], ainsi que trois autres cas, dont deux familiaux, dans d'autres études indépendantes [6,7]. MMP21 code une protéine probablement sécrétée car elle présente une région amino-terminale contenant un peptide signal 1 .…”

Section: Le Gène Mmp21unclassified

“…L'expression de cette métalloprotéase est observée dans de multiples tissus embryonnaires et adultes, ainsi que dans des tumeurs cancéreuses [8]. Les mutations rapportées ont été trouvées dans tous les domaines de la protéine (Figure 2) [5][6][7], démontrant que celleci doit être intègre pour fonctionner normalement.…”

Section: Le Gène Mmp21unclassified

“…Pour ces huit familles identifiées, aucun des malades . L'emplacement des mutations est symbolisé en-dessous de la protéine, avec en noir les mutations de l'article de Guimier et al [5], et en bleu les mutations rapportées dans deux autres articles [6,7]. nécessaires à l'arrimage et à la fusion des granules à la membrane plasmique [3,4] (➜).…”

Section: Le Gène Mmp21unclassified

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Un gène codant une métalloprotéase impliqué dans l’hétérotaxie

et al. 2016

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Prenatal and postnatal presentation of PRMT7 related syndrome: Expanding the phenotypic manifestations

Birnbaum

Yosha-Orpaz

Yanoov-Sharav

et al. 2018

American J of Med Genetics Pt A

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Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-L-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum.Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor. K E Y W O R D S developmental delay, pilocytic astrocytoma, prenatal ultrasound, PRMT7, systemic venous anomaly 1 | INTRODUCTION In 2015, Akawi et al. (2015) described six affected individuals from three families with variants in the protein arginine methyltransferase 7 (PRMT7) gene. The patients were part of a cohort of 4,125 families analyzed according to probabilistic genotype and phenotype matching, which gave rise to new genes. The associated clinical phenotype seen in these patients was considered a phenocopy of pseudohypoparathyroidism (PHP; MIM 103580; also known as Albright hereditary osteodystrophy. In 2017, Kernohan et al. (2017) reported a 6-year-old male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism, and seizures who was diagnosed with a homozygous 15,309 bp deletion encompassing the transcription start site of the PRMT7 gene. Agolini et al. (2018) described three additional patients with severe/moderate intellectual disability, short stature, brachydactyly, and mild dysmorphic features. Recently, Valenzuela et al. (2018) described a 2-yearold girl with intellectual disability, facial dysmorphism, short stature,brachydactyly, and hearing loss with two mutations inPRMT7. In this report, we describe, the prenatal, postnatal, and pathological findings of two male sibs found to harbor a homozygous PRMT7 mutation. | PATIENTS AND METHODSThis is a retrospective analysis of data from two consecutiv...

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Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Cited by 142 publications

References 42 publications

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Un gène codant une métalloprotéase impliqué dans l’hétérotaxie

Prenatal and postnatal presentation of PRMT7 related syndrome: Expanding the phenotypic manifestations

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