A novel HYLS1 homozygous mutation in living siblings with Joubert syndrome

Abstract

The p.Asp211Gly homozygous HYLS1 mutation is so far known to cause only hydrolethalus syndrome, a lethal malformation syndrome. We report living sibling patients with a homozygous no-stop mutation in exon 4 of HYLS1, NM_145014.2:c.900A>C (p.Ter300TyrextTer11) in the second decade of life. The proband has Joubert syndrome (JS). The younger brother also has JS and an enlarged posterior fossa that was initially diagnosed as Dandy-Walker malformation. The present mutation is unique as it affects the stop codon. The product protein HYLS1 plays an essential role in the formation of the primary cilium. This report provides insight into the spectrum of disorders involving midline brain defects closely related to cilium dysfunction or ciliopathy.

Challenges in detecting genomic copy number aberrations using next-generation sequencing data and the eXome Hidden Markov Model: a clinical exome-first diagnostic approach

“…NGS analysis of the 34 patients yielded 16 possible candidate SNVs, some of which were previously reported. 10–14 …”

“…Indeed, we identified 24 possible disease-causing SNVs in 61 patients with developmental delays of unknown etiology, some of which were reported elsewhere. 10–14 Therefore, the genes selected by this panel were strongly relevant to Mendelian diseases. This finding led to the consideration that CNVs in the genetic regions targeted by the TruSight One sequencing panel (Illumina) could have disease-causing traits in most cases.…”

“…The sequence library was constructed using 50 ng of genomic DNA, and the 151-bp paired-end reads were sequenced using the MiSeq next-generation sequencer (Illumina) as previously described. 10–14 The extracted data were mapped to a reference genome using the BWA Enrichment v1.0 cloud software (Illumina). GRCh37/hg19 was used as the reference sequence in this study.…”

“…In this study, clinical exome sequencing was performed for 61 patients with developmental delays of unknown etiology and 24 possible disease-causing SNVs were detected; some of the novel SNVs were reported elsewhere. 10–14 The remaining samples, which showed no possible candidate variants, might contain pathogenic CNVs. Thus, these samples were analyzed using NGS data extracted with a targeted re-sequencing approach.…”

Clinical and genetic heterogeneity of primary ciliopathies (Review)

“…depending on the additional clinical characteristics, JS (MIM, 213300) has been classified into several groups as follows: i) Pure or classic JS, characterized by hypotonia, developmental delay, abnormal eye movements, breathing abnormalities, ataxia and Id; ii) JS with ocular defects, including retinal dystrophy or LcA; iii) JS with renal defects (NPHP); iv) JS with oculorenal defects, also named cerebello-oculorenal syndrome, comprising SLSN (retinal dystrophy, LcA and NPHP) associated with MTS, and dekaban-Arima syndrome (cerebrooculohepatorenal syndrome) characterized by chorioretinal coloboma or retinal dystrophy, PKD, MTS and hepatic fibrosis in some cases; v) JS with congenital hepatic fibrosis; vi) JS with congenital hepatic fibrosis and associated chorioretinal coloboma, also known as cOAcH syndrome; and vii) JS with orofaciodigital defects, including a lobulated or bifid tongue, hamartomas, cleft lip and/or palate and polydactyly, also known as orofaciodigital syndrome type VI (83,87). To date, ~40 causative genes covering >90% of clinical subjects have been identified (146)(147)(148)(149)(150)(151)(152).…”