Dataset Information

Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.

ABSTRACT: Jalili syndrome is a rare multisystem disorder with the most prominent features consisting of cone-rod dystrophy and amelogenesis imperfecta. Few cases have been reported in the Americas. Here we describe a case series of patients with Jalili syndrome examined at the National Eye Institute's Ophthalmic Genetics clinic between 2016 and 2018. Three unrelated sporadic cases were systematically evaluated for ocular phenotype and determined to have cone-rod dystrophy with bull's eye maculopathy, photophobia, and nystagmus. All patients had amelogenesis imperfecta. Two of these patients had Guatemalan ancestry and the same novel homozygous CNNM4 variant (p.Arg236Trp c.706C > T) without evidence of consanguinity. This variant met likely pathogenic criteria by the American College of Medical Genetics guidelines. An additional patient had a homozygous deleterious variant in CNNM4 (c.279delC p.Phe93Leufs*31), which resulted from paternal uniparental isodisomy for chromosome 2p22-2q37. This individual had additional syndromic features including developmental delay and spastic diplegia, likely related to mutations at other loci. Our work highlights the genotypic variability of Jalili syndrome and expands the genotypic spectrum of this condition by describing the first series of patients seen in the United States.

SUBMITTER: Prasov L

PROVIDER: S-EPMC8041260 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.

Prasov Lev L Ullah Ehsan E Turriff Amy E AE Warner Blake M BM Conley Julie J Mark Paul R PR Hufnagel Robert B RB Huryn Laryssa A LA

American journal of medical genetics. Part A 20200205 3

Jalili syndrome is a rare multisystem disorder with the most prominent features consisting of cone-rod dystrophy and amelogenesis imperfecta. Few cases have been reported in the Americas. Here we describe a case series of patients with Jalili syndrome examined at the National Eye Institute's Ophthalmic Genetics clinic between 2016 and 2018. Three unrelated sporadic cases were systematically evaluated for ocular phenotype and determined to have cone-rod dystrophy with bull's eye maculopathy, phot ...[more]

PMID: 32022389

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Project description:Biallelic pathogenic variants in RAB3GAP2 cause Warburg Micro syndrome (WARBM) and Martsolf syndrome (MS), two rare, phenotypically overlapping disorders characterized by congenital cataracts, intellectual disability, and hypogonadism. Although the initial report documented hypergonadotropic hypogonadism (implying a gonadal defect), an adolescent girl with WARBM/MS was subsequently reported to have hypogonadotropic hypogonadism (implying a central defect in either the hypothalamus or anterior pituitary). However, in adult MS, hypogonadotropism has not been convincingly demonstrated. Additionally, the correlation between the pathogenic severity of variants in RAB3GAP2 and the phenotypic severity also remains unclear. Here we present a clinical report of a woman with congenital cataracts, apparent intellectual disability, and pubertal failure who underwent exome sequencing (ES) to determine a precise molecular diagnosis. Reproductive phenotypes reported previously in individuals with MS and the genotypic spectrum of previous RAB3GAP2 variants were also reviewed. The ES identified pathogenic compound heterozygous RAB3GAP2 variants (c.387-2A > G; p.(Arg428Glu)) combined with her phenotypic features, which enabled a unifying molecular diagnosis of MS. Reproductive evaluation confirmed a normosmic idiopathic hypogonadotropic hypogonadism. Review of the RAB3GAP2 allelic spectrum in WARBM/MS suggests that although variants resulting in complete abrogation of RAB3GAP2 protein function cause severe WARBM, variants associated with partially preserved RAB3GAP2 function cause milder MS. This report expands the genotypic and phenotypic spectrum of MS and demonstrates hypogonadotropic hypogonadism as a key pathophysiologic abnormality in MS. Genotype-phenotype associations of previously reported RAB3GAP2 variants indicate that variants that fully abolish RAB3GAP2 function result in WARBM, whereas MS is associated with variants of lesser severity with residual RAB3GAP2 function.

Dataset Information

Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.

Publications

Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.

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