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Lee, Oh, Yoon, and Yoon: Whole Exome Sequencing in a Korean Child with Joubert Syndrome-related Disorders


Joubert syndrome and Joubert syndrome-related disorders (JSRDs) are rare autosomal recessive or X-linked disorders characterized by cerebellar vermis hypoplasia and a brain stem malformation, which presents as the “molar tooth sign” in magnetic resonance imaging (MRI). JSRDs are a group of clinically heterogeneous conditions that exhibit neurological manifestations and multiple organ involvement. JSRDs are also genetically heterogeneous, and approximately 20 causative genes that account for 45% of JSRDs have been identified. A 7-yr-old boy visited Wonkwang University Sanbon Hospital with the following presentations: no ocular fixation, ataxia, growth retardation, and hypotonia. Physical examination revealed facial dysmorphism, spindle shaped fingers, and height (99 cm) and weight (13 kg) below the third percentile. Ophthalmic examination revealed retinal dystrophy. A diagnosis of JSRDs was made based on clinical and brain MRI findings. We found two heterozygous variants c.2945 G>T; p.Arg982Met (G>T) and c.2216dupA; p.Phe740Valfs∗2 (dupA) in AHI1, and a heterozygous c.3973C>T; p.Arg1325Trp (C>T) variant in KIF7 by whole exome sequencing (WES). Genetic analysis on the proband's father revealed that he had both AHI1 variants, but did not have the KIF7 variant, which was inconsistent with autosomal recessive inheritance. Therefore, the G>T variant and C>T variant were presumed to be of “uncertain significance.” Furthermore, one novel dupA variant was interpreted as “pathogenic,” while the second allele was not detected. Caution should be exercised while interpreting the significance of variants detected by WES. In addition, the involvement of genes other than the 20 known ones will require further investigation to elucidate the pathogenesis of JSRDs.


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Fig. 1.
Brain magnetic resonance imaging showing the typical “molar tooth sign” attributed to cerebellar vermis hypoplasia and brainstem malformation.
Fig. 2.
Sequencing data from the variant alleles: (A) c.3973C>T (C>T) variant of KIF7 and (B) c.2945G>T (G>T) and c.2216dupA (dupA) variants of AHI1 were confirmed by Sanger sequencing in the proband and his father.Abbreviations: w/t, wild type; NT, no test.
Table 1.
Joubert syndrome (JBTS)-related genes
Type OMIM (Phenotype) Gene Locus Inheritance
JBTS1 213300 INPP5E 9q34.3 Autosomal recessive
JBTS2 608091 TMEM216 11q12.2 Autosomal recessive
JBTS3 608629 AHI1 6q23.3 Autosomal recessive
JBTS4 609583 NPHP1 2q13 Autosomal recessive
JBTS5 610188 CEP290 12q21.32 Autosomal recessive
JBTS6 610688 TMEM67 8q22.1 Autosomal recessive
JBTS7 611560 RPGRIP1L 16q12.2 In progress
JBTS8 612291 ARL13B 3q11.1 In progress
JBTS9 612285 CC2D2A 4p15.32 Autosomal recessive
JBTS10 300804 OFD1 Xp22.2 X-linked recessive
JBTS11 613820 TTC21B 2q24.3 In progress
JBTS12 200990 KIF7 15q26.1 Autosomal recessive
JBTS13 614173 TCTN1 12q24.11 Autosomal recessive
JBTS14 614424 TMEM237 2q33.1 Autosomal recessive
JBTS15 614464 CEP41 7q32.2 Autosomal recessive
JBTS16 614465 TMEM138 11q12.2 Autosomal recessive
JBTS17 614615 C5orf42 5p13.2 Autosomal recessive
JBTS18 614815 TCTN3 10q24.1 Autosomal recessive
JBTS19 614844 ZNF423 16q12.1 Autosomal dominant
JBTS20 614970 TMEM231 16q23.1 Autosomal recessive
JBTS21 615636 CSPP1 8q13.2 Autosomal recessive
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