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.

Structural and functional comparison of magnesium transporters throughout evolution

“…It is expressed at the basolateral membrane of colonic enterocytes and facilitates Mg 2+ extrusion towards the blood compartment. Interestingly, patients suffering Jalili syndrome due to dominant mutations in the CNNM4 gene do not develop serum Mg 2+ disturbances, rather defects in amelogenesis and cone-rod dystrophy [ 125 , 126 ].…”

Dentofacial manifestations in a child with Jalili syndrome

“…Mental retardation and muscular overgrowth are other features described in patients with JS 17 . The child in the present case was diagnosed with the global developmental delay and exhibited significant developmental defects of the ectodermal derivatives.…”

“…Mental retardation and muscular overgrowth are other features described in patients with JS. 17 The child in the present case was diagnosed with the global developmental delay and exhibited significant developmental defects of the ectodermal derivatives. A brief compendium of the differential diagnosis has been presented, which can be inferred while navigating the array of conditions with known co-occurrence with Amelogenesis Imperfecta (Table 1).…”

Novel homozygous nonsynonymous variant of CNNM4 gene in a Chinese family with Jalili syndrome

“…Jalili syndrome (JS) (OMIM # 217080), first described by Jalili and Smith in 1988 in a large Arab consanguineous family in Gaza strip, is a rare autosomal‐recessive inherited disease (Jalili & Smith, 1988 ). It has also been reported in Moroccan, Iranian, Polish, Kosovan, American, Turkish, Scotland, Lebanon, Guatemalan, Brazilian, Indian, and Chinese populations (Maia et al, 2018 ; Parry et al, 2009 ; Polok et al, 2009 ; Prasov et al, 2020 ; Purwar et al, 2015 ; Wang et al, 2015 ; Xu et al, 2015 ). The characteristic features of Jalili syndrome are Cone‐rod dystrophy (CRD) and amelogenesis imperfecta(AI) (Daneshmandpour et al, 2019 ).…”

“…So far, Jalili syndrome has been reported in approximately 34 families around the world, among which only one case was with Chinese ethnicity (Maia et al, 2018 ; Prasov et al, 2020 ; Wang et al, 2015 ). In the present study, we described the detailed clinical manifestations of a Chinese family with Jalili syndrome and investigated the underlying genetic defect.…”