[This corrects the article DOI: 10.3389/fgene.2022.943117.].

Introduction: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominant systemic vascular disease that primarily involves small arteries. Patients with CADASIL experience migraines, recurrent ischemic strokes, cognitive decline, and dementia. The NOTCH3 gene, which is located on chromosome 19p13.12, is one of the disease-causing genes in CADASIL. Herein, we investigate the genetic and phenotypic features in a Chinese CADASIL family with heterozygous NOTCH3 mutation. Methods and Results: In the family, the proband suffered from dizziness, stroke, and cognitive deficits. Brain magnetic resonance imaging (MRI) demonstrated symmetrical white matter lesions in the temporal lobe, outer capsule, lateral ventricle, and deep brain. Whole-exome sequencing identified a known missense mutation in the proband, c.397C>T (p.Arg133Cys), which was identified in his son and granddaughter using Sanger sequencing. The proband\'s younger brother and younger sister also have a history of cognitive impairment or cerebral infarction, but do not have this genetic mutation, which may highlight the impact of lifestyle on this neurological disease. Conclusion: We identified a known CADASIL-causing mutation NOTCH3 (c.397C>T, p.Arg133Cys) in a Chinese family. The clinical manifestations of mutation carriers in this family are highly heterogeneous, which is likely a common feature for the etiology of different mutations in CADASIL. Molecular genetic analyses are critical for accurate diagnosis, as well as the provision of genetic counselling for CADASIL.

Skeletal dysplasias (SDs) are common birth defects, but they are difficult to diagnose accurately according to only the limited phenotypic information available from ultrasound during the pregnancy. To evaluate the application of whole-exome sequencing (WES) and expand the data in the prenatal molecular diagnosis of fetuses with SDs, we collected 55 fetuses with SDs based on ultrasonographic features. WES of the fetuses or parent-fetus trio were subjected to sequential tests and produced a diagnostic yield of 64% (35/55). 65% (11/17) of families with a history of adverse pregnancies were diagnosed, 16 genes were involved and 37 different pathogenic or likely pathogenic variants were identified, including 14 novel variants, which were first reported in this study. De novo variants were identified in 21 cases (60%, 21/35) among the fetuses with a genetic diagnosis. The pathogenicity of two novel splice-site variants was confirmed by constructing minigene in vitro. Our results revealed that WES can provide new evidence for the relationship between the genotype and phenotype of fetuses with SDs, as well as broaden the mutation spectrum of detected genes, which is significant for prenatal diagnosis and genetic counseling.

Silver-Russell syndrome (SRS) is a rare, well-recognized disorder characterized by growth restriction, including intrauterine and postnatal growth. Most SRS cases are caused by hypomethylation of the paternal imprinting center 1 (IC1) in chromosome 11p15.5 and maternal uniparental disomy in chromosome 7 (UPD7). Here, we report on a Chinese family with a 4 year old male proband presenting with low birth weight, growth retardation, short stature, a narrow chin, delayed bone age, and speech delays, as a result of a rare molecular etiology. Whole-exome sequencing was conducted, and a novel de novo IGF2 splicing variant, NM_000612.4: c.157+5G > A, was identified on the paternal allele. In vitro functional analysis by RT-PCR and Sanger sequencing revealed that the variant leads to an aberrant RNA transcript lacking exon 2. Our results further confirm the IGF2 variant mediates SRS and expand the pathogenic variant and phenotypic spectrum of IGF2-mediated SRS. The results indicate that, beyond DNA methylation and UPD7 and CDKN1C variant tests, IGF2 gene screening should also be considered for SRS molecular diagnoses.