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The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome.

ABSTRACT: RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias with microcephalic osteodysplastic primordial dwarfism, type 1 having a more severe phenotype than Roifman syndrome. Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency. The features also overlap with Lowry Wood syndrome, another rare but well-defined skeletal dysplasia for which the genetic etiology has not been identified. Characteristic features include multiple epiphyseal dysplasia and microcephaly. Here, we describe three patients with Lowry Wood syndrome with biallelic RNU4ATAC pathogenic variants. This report expands the phenotypic spectrum for biallelic RNU4ATAC disorder causing variants and is the first to establish the genetic cause for Lowry Wood syndrome.

SUBMITTER: Farach LS

PROVIDER: S-EPMC6774248 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome.

Farach Laura S LS Little Mary E ME Duker Angela L AL Logan Clare V CV Jackson Andrew A Hecht Jaqueline T JT Bober Michael M

American journal of medical genetics. Part A 20171219 2

RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias with microcephalic osteodysplastic primordial dwarfism, type 1 having a more severe phenotype than Roifman syndrome. Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency. The features also overlap with Lowry Wood syndrome, another ...[more]

PMID: 29265708

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Project description:BackgroundPURA syndrome is rare autosomal dominant condition characterized by moderate to severe neurodevelopmental delay with absence of speech in nearly all patients and lack of independent ambulation in many. Early-onset problems include excessive hiccups, hypotonia, hypersomnolence, hypothermia, feeding difficulties, recurrent apneas, epileptic seizures, and abnormal nonepileptic movements. Other less common manifestations comprise congenital heart defects, urogenital malformations, and various skeletal, ophthalmological, gastrointestinal, and endocrine anomalies. Up to now, 78 individuals with PURA syndrome and 64 different pathogenic variants have been reported, but no clear-cut genotype-phenotype correlations have emerged so far. Herein, we report the clinical and molecular characterization of a 3-year-old girl with severe hypotonia, global developmental delay, and soft, loose skin, who came to our attention with a suspicion of cutis laxa (CL), which denotes another condition with variable neurodevelopmental problems.MethodsAmplicon-based whole exome sequencing was performed, and an in-house pipeline was used to conduct filtering and prioritization of variants. New prediction algorithms for indels were used to validate the pathogenicity of the PURA variant, and results were confirmed with the Sanger method. Finally, we collected clinical and mutational data of all PURA syndrome patients reported yet and compared the clinical features with those of our patient.ResultsClinical evaluation and biochemical investigations excluded CL and prompted to perform whole exome sequencing, which confirmed the absence of pathogenic variants in all CL-related genes and revealed the known PURA c.697_699del, p.(Phe233del) variant, identified hitherto in seven additional children with PURA syndrome.ConclusionsOur data expand the phenotypic spectrum of PURA syndrome by showing that it can be regarded as a differential diagnosis for cutis laxa in early infancy. Our patient and literature review emphasize that a wide clinical variability exists not only between individuals with different PURA variants, but also among patients with the same causal mutation.

Dataset Information

The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome.

Publications

The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome.

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