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Case Report: Second Report of Joubert Syndrome Caused by Biallelic Variants in IFT74.

ABSTRACT: Joubert syndrome (JBTS) is a rare ciliopathy characterized by developmental delay, hypotonia, and distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). We reported a 15-month-old female with dysmorphic features (flat nasal bridge, almond-shaped eye, and a minor midline notch in the upper lips), hypotonia, polydactyly, development delay, and MTS. Whole exome sequencing revealed biallelic heterozygous mutations c.535C>G(p.Q179E/c.853G>T) (p.E285^*) in IFT74, which were inherited from the parents. So far, only one article reported JBTS associated with IFT74 gene mutation, and this is the second report of the fifth patient with JBTS due to variants in IFT74. All five patients had developmental delay, postaxial polydactyly, subtle cleft of the upper lip, hypotonia, and MTS, but notably without renal and retinal anomalies or significant obesity, and they shared the same mutation c.535C>G(p.Q179E) in IFT74, and c.853G>T(p.E285^*) that we found was a new mutation in IFT74 that related with Joubert syndrome. Those findings highlight the need for the inclusion of IFT74 in gene panels for JBST testing.

SUBMITTER: Zhongling K

PROVIDER: S-EPMC8440907 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Case Report: Second Report of Joubert Syndrome Caused by Biallelic Variants in IFT74.

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