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Feeding difficulty is the dominant feature in 12 Chinese newborns with CHD7 pathogenic variants.

ABSTRACT: BACKGROUND:CHARGE syndrome is characterized by coloboma, heart defects, choanal atresia, growth retardation, genitourinary malformation and ear abnormalities. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is the major cause of CHARGE syndrome and is inherited in an autosomal dominant manner. Currently, the phenotype spectrum of CHARGE syndrome in neonatal population remain elusive. We aimed to investigate the phenotype spectrum of neonatal patients suspected to have CHARGE syndrome with pathogenic or likely pathogenic variants in the CHD7 gene. METHODS:We pooled next-generation sequencing data from the Neonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov Identifier: NCT02551081) in Children's Hospital of Fudan University. The pathogenicity of novel variants was analyzed by bioinformatic and genetic analyses. Clinical information collection, Sanger sequencing and follow-up interviews were performed when possible. Cranial MRI of these patients was performed, the volumes of different regions of the brain were analyzed. RESULTS:A total of 12 unrelated patients in our cohort were found with CHD7 variants. Eight patients received a firm clinical diagnosis of CHARGE syndrome (Bergmann criteria, Blake criteria, Verloes criteria and Hale criteria). Three patients did not match any diagnostic criteria, and no patients matched the Verloes criteria. Phenotype spectrum analysis found that feeding difficulty was the dominant feature among this neonatal cohort. Six novel variants in the CHD7 gene (Glu2408*, Lys651*, c.5607?+?1G?>?T, Leu373Val, Lys2005Asnfs*37 and Gln1991*) were identified, expanding the variant database of the CHD7 gene. Cranial MRI analysis revealed significant volume loss in cingulate gyrus, occipital lobe, and cerebellum and volume gain in the left medial and inferior temporal gyri anterior white matter parts. CONCLUSIONS:Based on a relatively unbiased neonatal cohort, we concluded that CHARGE syndrome and CHD7 gene variants should be suspected in newborns who have feeding difficulty, and one or more malformations. TRIAL REGISTRATION:Neonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov identifier: NCT02551081 ).

SUBMITTER: Chen X

PROVIDER: S-EPMC6543684 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Feeding difficulty is the dominant feature in 12 Chinese newborns with CHD7 pathogenic variants.

Chen Xiang X Yan Kai K Gao Yanyan Y Wang Huijun H Chen Guoqiang G Wu Bingbing B Qin Qian Q Yang Lin L Zhou Wenhao W

BMC medical genetics 20190530 1

<h4>Background</h4>CHARGE syndrome is characterized by coloboma, heart defects, choanal atresia, growth retardation, genitourinary malformation and ear abnormalities. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is the major cause of CHARGE syndrome and is inherited in an autosomal dominant manner. Currently, the phenotype spectrum of CHARGE syndrome in neonatal population remain elusive. We aimed to investigate the phenotype spectrum of neonatal patients suspected to have CHARGE ...[more]

PMID: 31146700

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Project description:Background: Homozygous and compound heterozygous mutations in HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, heterozygous pathogenic variants in HTRA1 were described in patients with autosomal dominant cerebral small vessel disease (CSVD). Here, we investigated the genetic variants in a cohort of Chinese patients with CSVD. Methods: A total of 95 Chinese index patients with typical characteristics of CSVD were collected. Whole exome sequencing was performed in the probands, followed by Sanger sequencing. Pathogenicity prediction software was applied to evaluate the pathogenicity of the identified variants. Results: We detected five heterozygous HTRA1 pathogenic variants in five index patients. These pathogenic variants included four known variants (c.543delT, c.854C>T, c.889G>A, and c.824C>T) and one novel variant (c.472 + 1G>A). Among them, c.854C>T, c.824C>T, and c.472 + 1G>A have never been reported in China and c.889G>A was once reported in homozygous but never in heterozygous. Three of them were distributed in exon 4, one in exon 2, and another splicing variant in intron 1. Four out of five probands presented typical features of CARASIL but less severe. The common clinical features included lacunar infarction, cognitive decline, alopecia, and spondylosis. All of them showed leukoencephalopathy, and the main involved cerebral area include periventricular and frontal area, centrum semiovale, thalamus, and corpus callosum. Anterior temporal lobes and external capsule involvement were also observed. Three probands had intracranial microbleeds. Conclusion: Our study expanded the mutation spectrum of HTRA1, especially in Chinese populations, and provided further evidence for "hot regions" in exon 1-4, especially in exon 4, in heterozygous HTRA1 pathogenic variants. Our work further supported that patients with heterozygous HTRA1 pathogenic variants presented with similar but less-severe features than CARASIL but in an autosomal dominantly inherited pattern.

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Feeding difficulty is the dominant feature in 12 Chinese newborns with CHD7 pathogenic variants.

Publications

Feeding difficulty is the dominant feature in 12 Chinese newborns with CHD7 pathogenic variants.

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