Gillespiesyndrome in a South Asian child: a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features. Gillespiesyndrome is a rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia, non-progressive cerebellar ataxia and intellectual disability. Homozygous and heterozygous pathogenic variant c.7786_7788delAAG p.(Lys2596del) in the ITPR1 gene. The report of this child with molecular confirmation of Gillespiesyndrome highlights the need for careful evaluation of ophthalmological and neurological features in patients that enables correct clinical diagnosis. The availability of genetic testing enables more accurate counseling of the parents and patients regarding recurrence
Identification of novel and hotspot mutations in the channel domain of ITPR1 in two patients with Gillespiesyndrome ITPR1 encodes an intracellular receptor for inositol 1,4,5-trisphosphate (InsP3) which is highly expressed in the cerebellum and is involved in the regulation of Ca2+ homeostasis. Missense mutations in the InsP3-binding domain (IRBIT) of ITPR1 are frequently associated with early onset cerebellar atrophy. Gillespiesyndrome is characterized by congenital ataxia, mild to moderate intellectual disability and iris hypoplasia. Dominant or recessive ITPR1 mutations have been recently associated with this form of syndromic ataxia. We performed next generation sequencing in two simplex families with Gillespiesyndrome and identified de novo pathological mutations localized in the C
A Restricted Repertoire of De Novo Mutations in ITPR1 Cause GillespieSyndrome with Evidence for Dominant-Negative Effect. Gillespiesyndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited
Recessive and Dominant De Novo ITPR1 Mutations Cause GillespieSyndrome. Gillespiesyndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode , did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespiesyndrome, further extending
Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or GillespieSyndrome We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespiesyndrome (iris with Gillespiesyndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespiesyndrome). Fourteen of these mutations presented in the known
Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design. The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP ) receptor type 1 (IP R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespiesyndrome (GLSP), and severe pontine/cerebellar
is reported featuring ataxia in association with other clinical features. A few conditions such as Gillespiesyndrome include 1 or 2 additional features (eg, intellectual disability, partial aniridia), while other conditions such as Joubert syndrome (ie, hypotonia, hyperventilation, facial dysmorphism, retinal dystrophy, renal involvement) and COACH syndrome (ie, cerebellar hypoplasia, oligophrenia, ataxia Autosomal dominant X-linked Ataxia syndromes with cerebellar hypoplasia (eg, Gillespiesyndrome) Partial
is reported featuring ataxia in association with other clinical features. A few conditions such as Gillespiesyndrome include 1 or 2 additional features (eg, intellectual disability, partial aniridia), while other conditions such as Joubert syndrome (ie, hypotonia, hyperventilation, facial dysmorphism, retinal dystrophy, renal involvement) and COACH syndrome (ie, cerebellar hypoplasia, oligophrenia, ataxia Autosomal dominant X-linked Ataxia syndromes with cerebellar hypoplasia (eg, Gillespiesyndrome) Partial
is reported featuring ataxia in association with other clinical features. A few conditions such as Gillespiesyndrome include 1 or 2 additional features (eg, intellectual disability, partial aniridia), while other conditions such as Joubert syndrome (ie, hypotonia, hyperventilation, facial dysmorphism, retinal dystrophy, renal involvement) and COACH syndrome (ie, cerebellar hypoplasia, oligophrenia, ataxia Autosomal dominant X-linked Ataxia syndromes with cerebellar hypoplasia (eg, Gillespiesyndrome) Partial
is reported featuring ataxia in association with other clinical features. A few conditions such as Gillespiesyndrome include 1 or 2 additional features (eg, intellectual disability, partial aniridia), while other conditions such as Joubert syndrome (ie, hypotonia, hyperventilation, facial dysmorphism, retinal dystrophy, renal involvement) and COACH syndrome (ie, cerebellar hypoplasia, oligophrenia, ataxia Autosomal dominant X-linked Ataxia syndromes with cerebellar hypoplasia (eg, Gillespiesyndrome) Partial
aniridia (WAGR syndrome and Gillespiesyndrome).The major gene responsible for autosomal dominant forms of congenital aniridia is PAIRED BOX GENE 6 (PAX6) (MIM#607108) with over 500 pathogenic variants reported to date.Congenital aniridia is therefore a rare, pan-ocular disease associating systemic manifestations, with a variable phenotype and genotype.This study aims to identify eye and systemic
Non-progressive cerebellar ataxia, aplasia of pupillary zone of iris, and mental subnormality (Gillespie'ssyndrome) affecting 3 members of a non-consanguineous family in 2 generations. A family is reported in which a brother and sister both showed non-progressive cerebellar ataxia, aplasia of the pupillary zone of the iris, and mild mental subnormality. These clinical findings were similar