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1.
J Med Genet ; 59(9): 888-894, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34675124

RESUMO

BACKGROUND: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies. METHODS: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes. RESULTS: Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents. CONCLUSION: Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.


Assuntos
Anormalidades Múltiplas , Ataxia Cerebelar , Anormalidades do Olho , Deficiência Intelectual , Doenças Renais Císticas , Anormalidades Múltiplas/genética , Ataxia Cerebelar/genética , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Anormalidades do Olho/genética , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/genética , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Masculino , Fenótipo , Proteínas Repressoras/genética , Retina/anormalidades
2.
Am J Hum Genet ; 101(2): 291-299, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777934

RESUMO

Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c.145delG [p.Glu49Argfs∗14]) or compound-heterozygous variants (c.360dupC [p.Glu121Argfs∗7] and c.1880C>T [p. Ala627Val]). The clinical phenotypes of the three individuals are strikingly similar: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12. Protein transport from the endoplasmic reticulum to and through the Golgi was delayed. TRAPPC12 is a member of the TRAPP protein complex, which functions in membrane trafficking. Variants in several other genes encoding members of the TRAPP complex have been associated with overlapping clinical presentations, indicating shared and distinct functions for each complex member. Detailed understanding of the TRAPP-opathies will illuminate the role of membrane protein transport in human disease.


Assuntos
Encefalopatias/genética , Retículo Endoplasmático/metabolismo , Complexo de Golgi/patologia , Proteínas de Membrana Transportadoras/genética , Transporte Proteico/genética , Fatores de Transcrição/genética , Atrofia/patologia , Sequência de Bases , Encéfalo/patologia , Encefalopatias/patologia , Células Cultivadas , Pré-Escolar , Exoma/genética , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Transporte Proteico/fisiologia , Análise de Sequência de DNA
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