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Novel compound variants of the TMTC3 gene cause cobblestone lissencephaly-like syndrome: A case report.

ABSTRACT: Biallelic variants in the transmembrane O-mannosyltransferase targeting cadherins 3 (TMTC3) gene have been reported to cause two distinct types of neuron migration defect diseases, known as cobblestone lissencephaly (COB) and periventricular nodular heterotopia (PVNH), combined with intellectual disability and nocturnal seizures. The aim of the current study was to identify the genetic cause of a 22-month-old Chinese boy who presented with white matter plaques, a small frontal lobe, myelin dysplasia, microcephaly, psychomotor delay, language development delay, truncal hypotonia, intractable epilepsy, infantile spasm and bilateral single transverse palmar creases. Whole-exome sequencing revealed novel heterozygous variant compounds in the TMTC3 gene (c.1123G>A, p.Glu375Lys and c.1126_1129del, p.Arg376Tyrfs*13). Most of the clinical features of the patient are consistent with COB. However, the deformities in the brain (white matter plaques, small frontal lobe and myelin dysplasia) in the patient were more severe compared with those generally exhibited by PVNH, but less severe compared with those presented by COB. Moreover, the patient exhibited bilateral single transverse palmar creases, which, to the best of our knowledge, have not been described previously in patients with a TMTC3 variation. In summary, the current study reported a pediatric Chinese patient with COB-like syndrome caused by TMTC3 gene variations. The present results indicated that variation in the TMTC3 gene can lead to highly variable clinical phenotypes.

SUBMITTER: Liu G

PROVIDER: S-EPMC7507045 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Novel compound variants of the <i>TMTC3</i> gene cause cobblestone lissencephaly-like syndrome: A case report.

Liu Guanghua G Zhou Qing Q Lin Han H Li Niu N Ye Hong H Wang Jian J

Experimental and therapeutic medicine 20200916 5

Biallelic variants in the transmembrane O-mannosyltransferase targeting cadherins 3 (<i>TMTC3</i>) gene have been reported to cause two distinct types of neuron migration defect diseases, known as cobblestone lissencephaly (COB) and periventricular nodular heterotopia (PVNH), combined with intellectual disability and nocturnal seizures. The aim of the current study was to identify the genetic cause of a 22-month-old Chinese boy who presented with white matter plaques, a small frontal lobe, myeli ...[more]

PMID: 32973946

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Project description:BackgroundLissencephaly (LIS) is a cortical malformation, characterized by smooth or nearly smooth cerebral surface and a shortage of gyral and sulcal development, which is caused by deficient neuronal migration during embryogenesis. Neuronal migration involves many gene products, among which is the product of the PAFAH1B1 gene, associated with this disease. LIS is a rare disease, characterized by low population frequency, and with non-specific clinical symptoms such as early epilepsy, developmental delay or cerebral palsy-like motor problems. Given that high-throughput sequencing techniques have been improving diagnosis, we have chosen this technique for addressing this patient.Case presentationWe present the case of a seven years old male patient with an undiagnosed rare disease, with non-specific clinical symptoms possibly compatible with lissencephaly. The patient was enrolled in a study that included the sequencing of his whole genome. Sequence data was analyzed following a bioinformatic pipeline. The variants obtained were annotated and then subjected to different filters for prioritization. Also mitochondrial genome was analyzed. A novel candidate frameshift insertion in known PAFAH1B1 gene was found, explaining the index case phenotype. The assessment through in silico tools reported that it causes nonsense mediated mechanisms and that it is damaging with high confidence scores. The insertion causes a change in the reading frame, and produces a premature stop codon, severely affecting the protein function and probably the silencing of one allele. The healthy mother did not carry the mutation, and the unaffected father was not available for analysis.ConclusionsThrough this work we found a novel de novo mutation in LIS1/PAFAH1B1 gene, as a likely cause of a rare disease in a young boy with non-specific clinical symptoms. The mutation found correlates with the phenotype studied since the loss of function in the gene product has already been described in this condition. Since there are no other variants in the PAFAH1B1 gene with low population frequency and due to family history, a de novo disease mechanism is proposed.

Project description:BACKGROUND:Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION:We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION:This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.

Dataset Information

Novel compound variants of the TMTC3 gene cause cobblestone lissencephaly-like syndrome: A case report.

Publications

Novel compound variants of the <i>TMTC3</i> gene cause cobblestone lissencephaly-like syndrome: A case report.

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