Mutation of
            <i>TBCK</i>
            causes a rare recessive developmental disorder

Guerreiro, Rita; Brown, Rachel E.; Dian, Donnai; Goede, Christian de; Brás, José; Mole, Sara

doi:10.1212/nxg.0000000000000076

Cited by 22 publications

(31 citation statements)

References 8 publications

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“…In the case of CABMHF3, we identified a homozygous stop-gain (Guerreiro et al, 2016). They also had epilepsy and similar distinctive facial features, and the two youngest siblings had signs of precocious puberty.…”

Section: Loss-of-function Variants Outside Of Lsd Candidate Genesmentioning

confidence: 85%

Using whole‐exome sequencing to investigate the genetic bases of lysosomal storage diseases of unknown etiology

et al. 2017

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Lysosomes are membrane-bound, acidic eukaryotic cellular organelles that play important roles in the degradation of macromolecules. Mutations that cause the loss of lysosomal protein function can lead to a group of disorders categorized as the lysosomal storage diseases (LSDs). Suspicion of LSD is frequently based on clinical and pathologic findings, but in some cases, the underlying genetic and biochemical defects remain unknown. Here, we performed whole-exome sequencing (WES) on 14 suspected LSD cases to evaluate the feasibility of using WES for identifying causal mutations. By examining 2,157 candidate genes potentially associated with lysosomal function, we identified eight variants in five genes as candidate disease-causing variants in four individuals. These included both known and novel mutations. Variants were corroborated by targeted sequencing and, when possible, functional assays. In addition, we identified nonsense mutations in two individuals in genes that are not known to have lysosomal function. However, mutations in these genes could have resulted in phenotypes that were diagnosed as LSDs. This study demonstrates that WES can be used to identify causal mutations in suspected LSD cases. We also demonstrate cases where a confounding clinical phenotype may potentially reflect more than one lysosomal protein defect.

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Section: Loss-of-function Variants Outside Of Lsd Candidate Genesmentioning

confidence: 85%

Using whole‐exome sequencing to investigate the genetic bases of lysosomal storage diseases of unknown etiology

et al. 2017

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“…Bhoj et al [] and Chong et al [] added another 18 affected individuals with TBCK deficiency to the reported families [Bhoj et al, ; Chong et al, ]. Guerreiro et al [] characterized a family with three siblings affected by a severe, yet viable, congenital disorder. All affected siblings had epilepsy with onset between 9 months to 3 years, profound hypotonia, strabismus, and global delay.…”

Section: Discussionmentioning

confidence: 99%

“…Chong et al [] found that loss of TBCK function affects this signaling network in a manner opposite of what is observed in other mTOR‐related disorders, and that over‐inhibition of the mTOR pathway might lead to this distinct severe phenotype. Most affected individuals show very poor, if any, normal psychomotor development, poor speech, and inability to walk independently [Bhoj et al, ; Guerreiro et al, ]. We describe the evolution of the phenotype in two affected siblings with a novel homozygous mutation in the TBCK gene, born to an Arab‐Moslem family living in northern Israel.…”

Section: Introductionmentioning

confidence: 99%

TBCK‐related intellectual disability syndrome: Case study of two patients

Mandel

Khayat

Chervinsky

et al. 2016

American J of Med Genetics Pt A

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There is a significant level of genetic heterogeneity underlying the phenotype of nonspecific hypotonia with severe intellectual disability. Exome sequencing has proven to be a powerful tool for identifying the underlying molecular basis of such nonspecific, abnormal neurological phenotypes. Mutations in the TBCK gene have been reported associated with very poor, if any, psychomotor development, poor speech, and inability to walk independently. We describe the long-term phenotypic evolution of a severe nonspecific neurodevelopmental disorder in two siblings born to an Arab-Moslem family living in northern Israel. Exome sequencing led to identification of a novel homozygous mutation: c.1854delT in the TBCK gene. Abnormal elevated β-HCG was found in the maternal serum during the two pregnancies, a finding that has not been reported before. These individuals present with severe intellectual disability, no speech, hypotonia, convulsions, and lack of any independent daily skills. © 2016 Wiley Periodicals, Inc.

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“…The introduction of next-generation sequencing (NGS) technologies into both research and clinical settings has been instrumental in the detection of many new disease-causing genes, particularly for rare diseases and cancers (Guerreiro et al, 2016;Rotunno et al, 2016;Tetzlaff et al, 2016). NGS, which encompasses targeted gene panels and wholeexome/whole-genome sequencing, is novel in that it allows the analysis of numerous genes in a single test (Rabbani, Tekin, & Mahdieh, 2014).…”

Section: Introductionmentioning

confidence: 99%