Lab Med Online.  2017 Jan;7(1):45-48. 10.3343/lmo.2017.7.1.45.

Whole Exome Sequencing in a Korean Child with Joubert Syndrome-related Disorders

• Lee JH
• Oh IK
• Yoon MJ
• Yoon KH

• KMID: 2363007
• DOI: http://doi.org/10.3343/lmo.2017.7.1.45

Abstract

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.

Keyword

Joubert syndrome; Whole exome sequencing; AHI1; KIF7

MeSH Terms

Alleles
Ataxia
Brain
Brain Stem
Cerebellar Vermis
Child*
Diagnosis
Exome*
Fathers
Fingers
Fixation, Ocular
Humans
Magnetic Resonance Imaging
Male
Muscle Hypotonia
Neurologic Manifestations
Physical Examination
Retinal Dystrophies
Tooth
Wills

Figure

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  Fig. 1. Brain magnetic resonance imaging showing the typical “molar tooth sign” attributed to cerebellar vermis hypoplasia and brainstem malformation.

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  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.

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