RPGRIP1L – Joubert syndrome 7

Biallelic variants in RPGRIP1L (HGNC:29168) cause Joubert syndrome 7 (MONDO:0012694), an autosomal recessive ciliopathy characterized by cerebellar vermis aplasia and the molar tooth sign (PMID:38013309). Affected individuals present with hypotonia, global developmental delay, oculomotor apraxia, and characteristic posterior fossa malformations.

In a reported Colombian pediatric case, whole-exome sequencing identified compound heterozygous RPGRIP1L variants c.697A>T (p.Lys233Ter) and c.3545del (p.Pro1182LeufsTer25), confirmed by Sanger sequencing with segregation in the parents (PMID:38013309). The patient manifested hypotonia, developmental delay, polydactyly, umbilical hernia, renal interstitial fibrosis, and ophthalmologic abnormalities including exotropia, astigmatism, and hyperopia.

In a cohort of 56 JS type B patients negative for AHI1, NPHP1, and CEP290, sequencing of RPGRIP1L revealed four distinct pathogenic alleles (c.1897T>C (p.Cys633Arg), c.3295-2A>G, c.1177G>A (p.Glu393Lys), c.1843A>C (p.Thr615Pro)) in five unrelated families, accounting for ~8–10% of cases (PMID:17960139). This series expanded the variant spectrum and confirmed autosomal recessive inheritance in multiple families.

Functional studies demonstrate that Rpgrip1l-deficient mouse embryos recapitulate ciliopathy phenotypes with impaired sonic hedgehog signaling and reduced proteasomal activity at the ciliary base, implicating haploinsufficiency as the disease mechanism (PMID:26150391). In Chlamydomonas, RPGRIP1L mutants exhibit aberrant ciliary gating and increased cytoplasmic protein accumulation in cilia, supporting a conserved role in transition zone integrity (PMID:30237221).

No conflicting reports have been published that refute the association of biallelic RPGRIP1L variants with Joubert syndrome 7.

Collectively, genetic and functional data support a Moderate ClinGen validity classification for RPGRIP1L in Joubert syndrome 7. RPGRIP1L should be included in diagnostic gene panels for AR Joubert syndromes. Key take-home: Identification of RPGRIP1L biallelic truncating and missense variants enables molecular diagnosis of JS7 and informs genetic counseling.

References

• Medicine • 2023 • Novel mutation in RPGRIP1L gene causing Joubert syndrome: A case report. PMID:38013309
• Kidney International • 2007 • Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis. PMID:17960139
• The Journal of Cell Biology • 2015 • The transition zone protein Rpgrip1l regulates proteasomal activity at the primary cilium. PMID:26150391
• Journal of Cell Science • 2018 • RPGRIP1L helps to establish the ciliary gate for entry of proteins. PMID:30237221

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