Abstract
BackgroundLowe syndrome is a rare X‑linked syndrome that is characterized by involvement of the eyes, central nervous system, and kidneys. The aim of the present study was to determine the molecular basis of four patients with congenital cataract, infantile congenital hypotonia, and proximal renal tubular defect.MethodsFour children who met the clinical manifestations of Lowe syndrome were enrolled in this study. Patients’ clinical information on eyes, central nervous system, kidneys, and family histories, etc., were reviewed and analyzed. After obtaining informed consent, we performed a mutation analysis of OCRL gene using direct sequencing. Because of failure of PCR amplification, low coverage shortread whole genome sequencing (CNVseq) analysis was performed on one proband. Real‐time PCR was subsequently performed to confirm the CNV that was detected from the CNVseq results.ResultsWe identified three OCRL allelic variants, including two novel missense mutations (c.1423C>T/p.Pro475Ser, c.1502T>G/p.Ile501Ser) and one recurrent nonsense mutation (c.2464C>T/p.Arg822Ter). Various bioinformatic tools revealed scores associated with potential pathogenic effects for the two missense variants, and protein alignments revealed that both variants affected an amino acid highly conserved among species. Since deletion of the entire gene was suspected in a patient, CNVseq was used, identifying an interstitial deletion to approximately 190 kb, encompassing OCRL, and SMARCA1 gene. Moreover, the hemizygous CNV was confirmed by qPCR. Reviewing another case reported in the literature, we found that the deletion of OCRL and nearby genes may contribute to a more severe phenotype and premature death.ConclusionsThis is the first report of an interstitial deletion encompassing OCRL and SMARCA1 gene in Lowe syndrome. Our results expand the spectrum of mutations of the OCRL gene in Chinese population. Moreover, whole‐genome sequencing presents a comprehensive and reliable approach for detecting genomic copy number variation in patients or carriers in the family with rare inherited disorders.
Highlights
Lowe syndrome (OMIM, #309000) is a multisystem disorder characterized by ocular abnormalities, neurological involve‐ ment, and renal dysfunction of the Fanconi type (Charnas, Bernardini, Rader, Hoeg, & Gahl, 1991)
Mutations in OCRL cause Dent disease 2 (OMIM, #300555), a milder phenotype that only results in proximal renal tubulopathy (Hoopes et al, 2005)
Most mutations associated with Lowe syndrome are mapped in exons 8–23, which comprises the inositol polyphosphate 5‐phosphatase, ASH and RhoGAP‐like domains, whereas the majority of mutations that cause Dent disease 2 are lo‐ cated in exons 1–7, which encompass the pleckstrin homology (PH) domain
Summary
Lowe syndrome (OMIM, #309000) is a multisystem disorder characterized by ocular abnormalities, neurological involve‐ ment, and renal dysfunction of the Fanconi type (Charnas, Bernardini, Rader, Hoeg, & Gahl, 1991). Exons 2–5 encode the pleckstrin homology (PH)‐like domain, exons 9–15 encode the 5‐phosphatase catalytic domain, and exons 16–22 encode the ASPM, SPD‐2, Hydin (ASH) and RhoGAP‐like domains of the OCRL protein (Faucherre et al, 2003; Mao et al, 2009; Peck, Douglas, Wu, & Burbelo, 2002). Since this time, more than 260 different nonsense, frameshift, splice site, or mis‐ sense mutations have been annotated for OCRL gene in the Human Gene Mutation Database Whole‐genome sequencing presents a comprehensive and reliable approach for detecting genomic copy number variation in patients or carriers in the family with rare inherited disorders
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
