CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms

Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to the recently identified CRB1 isoforms: a canonical long isoform A localized in Müller cells (12 exons) and a short isoform B predominant in photoreceptors (7 exons). Twenty-eight patients with early onset retinal dystrophy (EORD) consistently had a severe Müller impairment, with variable impact on the photoreceptors, regardless of isoform B expression. Among them, two patients expressing wild type isoform B carried one variant in exon 12, which specifically damaged intracellular protein interactions in Müller cells. Thirteen retinitis pigmentosa patients had mainly missense variants in laminin G-like domains and expressed at least 50% of isoform A. Eight patients with the c.498_506del variant had macular dystrophy. In one family homozygous for the c.1562C>T variant, the brother had EORD and the sister macular dystrophy. In contrast with the mouse model, these data highlight the key role of Müller cells in the severity of CRB1-related dystrophies in humans, which should be taken into consideration for future clinical trials.

Inherited Leukoencephalopathies

Leukoencephalopathies are disorders that selectively involve the white matter of the brain. Acquired causes of leukoencephalopathy include inflammatory, infectious, vascular, neoplastic, and toxic disorders. Hereditary leukoencephalopathies encompass conditions characterized by progressive destruction or loss of previously acquired central myelin (leukodystrophies) and conditions associated with impaired formation of myelin (dysmyelination or hypomyelination). The study of clinical features, neuroimaging patterns, and biochemical and neuropathologic features of leukoencephalopathies has led to the discovery of the genetic defects responsible for many of these conditions. Variations in phenotype-genotype correlation can make prediction of the underlying condition challenging. Despite recent advances in molecular studies, approximately 50% of patients with hereditary leukoencephalopathies remain without a diagnosis. A systematic approach to guide investigations is important for a diagnosis.

Prenatal findings of 2q13 Duplication and Deletion: Further Evidence for Lack of Phenotypic-Genotype Correlation

2q13 CNV was associated with various diseases, with a lack of consensus. By CMA analysis, we found that four fetuses had deletion in the proximal region of 2q13, one had duplication, and one had duplication in the distal region of 2q13; however, they had variable outcomes.

Novel FERMT3 and PTPRQ Mutations Associated with Leukocyte Adhesion Deficiency-III and Sensorineural Hearing Loss

Leukocyte adhesion deficiency-III (LAD-III) is a rare genetic disease caused by defective integrin activation in hematopoietic cells due to mutations in the FERMT3 gene. The PTPRQ gene encodes the protein tyrosine phosphatase receptor Q and is essential for the normal maturation and function of hair bundle in the cochlea. Homozygous PTPRQ mutations impair the stereocilia in hair cells which lead to nonsyndromic sensorineural hearing loss (SNHL) with vestibular dysfunction. Here, we report two novel pathogenic homozygous mutations found in two genes, FERMT3 and PTPRQ, in a Brazilian patient with LAD-III and SNHL, which may develop our understanding of the phenotype–genotype correlation and prognosis of patients with these rare diseases.

Multiple Acyl-CoA Dehydrogenase Deficiency with Variable Presentation Due to a Homozygous Mutation in a Bedouin Tribe

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect caused by a deficiency of the electron-transfer flavoprotein (ETF) or the electron-transfer flavoprotein dehydrogenase (ETFDH). There are three phenotypes of the disease, two neonatal forms and one late-onset. Previous studies have suggested that there is a phenotype–genotype correlation. We report on six patients from a single Bedouin tribe, five of whom were sequenced and found to be homozygous to the same variant in the ETFDH gene, with variable severity and age of presentation. The variant, NM_004453.3 (ETFDH): c.524G>A, p.(R175H), was previously recognized as pathogenic, although it has not been reported in the literature in a homozygous state before. R175H is located near the FAD binding site, likely affecting the affinity of FAD for EFT:QO. The single homozygous ETFDH pathogenic variant was found to be causing MADD in this cohort with an unexpectedly variable severity of presentation. The difference in severity could partly be explained by early diagnosis via newborn screening and early treatment with the FAD precursor riboflavin, highlighting the importance of early detection by newborn screening.

SnpRecode: A versatile and fast genotype recoding and correlation function

Genotype imputation is an essential tool used in genomic selection in plants and animals. A popular imputation tool used in animal genomics is FImpute. FImpute, however, accepts a specific genotype format and produces dosages whose conversion to VCF or Plink format requires multiple software packages in a pipeline with a large amount of processing time. We have developed SnpRecode as a helper tool that bridges the gap between regular genotype files and the FImpute imputation software by allowing for fast and seamless conversion of genotypes to-and-from FImpute format. SnpRecode also implements a fast genotype correlation function to estimate and plot the imputation accuracy. We run tests on 6,000 samples with a step of 1,000 to determine the performance of SnpRecode on various sample sizes and runtime and memory usage used as performance measures. The performance of SnpRecode was modest at 10sec/1,000 samples. Written in Python programming language, SnpRecode provides users with great flexibility in implementation with other software packages in a pipeline.

Novel 61-bp Indel of RIN2 Is Associated With Fat and Hatching Weight Traits in Chickens

The Ras and Rab interactor 2 (RIN2) gene, which encodes RAS and Rab interacting protein 2, can interact with GTP-bound Rab5 and participate in early endocytosis. This study found a 61-bp insertion/deletion (indel) in the RIN2 intron region, and 3 genotypes II, ID, and DD were observed. Genotype analysis of mutation sites was performed on 665 individuals from F2 population and 8 chicken breeds. It was found that the indel existed in each breed and that yellow feathered chickens were mainly of the DD genotype. Correlation analysis of growth and carcass traits in the F2 population of Xinghua and White Recessive Rock chickens showed that the 61-bp indel was significantly correlated with abdominal fat weight, abdominal fat rate, fat width, and hatching weight (P < 0.05). RIN2 mRNA was expressed in all the tested tissues, and its expression in abdominal fat was higher than that in other tissues. In addition, the expression of the RIN2 mRNA in the abdominal fat of the DD genotype was significantly higher than that of the II genotype (P < 0.05). The transcriptional activity results showed that the luciferase activity of the pGL3-DD vector was significantly higher than that of the pGL3-II vector (P < 0.01). Moreover, the results indicate that the polymorphisms in transcription factor binding sites (TFBSs) of 61-bp indel may affect the transcriptional activity of RIN2, and thus alter fat traits in chicken. The results of this study showed that the 61-bp indel was closely related to abdominal fat-related and hatching weight traits of chickens, which may have reference value for molecular marker-assisted selection of chickens.

Hypomyelination and Congenital Cataract: Clinical, Imaging, and Genetic Findings in Three Tunisian Families and Literature Review

Hypomyelination and congenital cataract (HCC) is characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. This autosomal recessive disorder is caused by homozygous variant in the FAM126A gene. Five consanguineous Tunisian patients, belonging to three unrelated families, underwent routine blood tests, electroneuromyography, and magnetic resonance imaging of the brain. The direct sequencing of FAM126A exons was performed for the patients and their relatives. We summarized the 30 previously published HCC cases. All of our patients were carriers of a previously reported c.414 + 1G > T (IVS5 + 1G > T) variant, but the clinical spectrum was variable. Despite the absence of a phenotype–genotype correlation in HCC disease, screening of this splice site variant should be performed in family members at risk.