BACKGROUND: Periventricular nodular heterotopia-7 (PVNH7) is a neurodevelopmental disorder associated with improper neuronal migration during neurogenesis in cortex development caused by pathogenic variants in the NEDD4L gene.
UNASSIGNED: We report the case of a polystigmatized 2-year-old boy having significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The patient showed also distinct symptoms falling outside PVNH7 symptomatology, also present in the proband\'s older brother, such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus. In addition, the patient suffered from many other symptoms.
UNASSIGNED: The boy, his brother and their parents were subjected to whole-exome sequencing. Because of uncertainties in symptomatology and inheritance pattern, the top-down approach was hard to apply. Using the bottom-up approach, we identified a known pathogenic variant, NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys, in the proband\'s genome that absented in any other analyzed family member, suggesting its de novo origin.
RESULTS: The patient was treated with Convulex 300 mg/mL for the successful seizure control and Euthyrox 25mg for the treatment of thyroid malfunction. He also took various supplements for the metabolism support and digestion regulation. Moreover, the patient underwent the corrective surgeries of cleft palate and talipes equinovarus.
CONCLUSIONS: We successfully identified the causative mutation NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys explaining symptoms overlapping those reported for PVNH7. Symptoms shared with the brother were not explained by this variant, since he was not a carrier of the pathogenic NEDD4L variant. These are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family, highlighting thus the importance of thorough evaluation of symptomatology and genomic findings in affected and unaffected family members, when such data are available.

Recently, a recessively inherited intronic repeat expansion in replication factor C1 (RFC1) was identified in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Here, we describe a Japanese case of genetically confirmed CANVAS with autonomic failure and auditory hallucination. The case showed impaired uptake of iodine-123-metaiodobenzylguanidine and 123I-ioflupane in the cardiac sympathetic nerve and dopaminergic neurons, respectively, by single-photon emission computed tomography. Long-read sequencing identified biallelic pathogenic (AAGGG)n nucleotide repeat expansion in RFC1 and heterozygous benign (TAAAA)n and (TAGAA)n expansions in brain expressed, associated with NEDD4 (BEAN1). Enrichment of the repeat regions in RFC1 and BEAN1 using a Cas9-mediated system clearly distinguished between pathogenic and benign repeat expansions. The haplotype around RFC1 indicated that the (AAGGG)n expansion in our case was on the same ancestral allele as that of European cases. Thus, long-read sequencing facilitates precise genetic diagnosis of diseases with complex repeat structures and various expansions.

We report on the case of a 77-year-old male with genetically proven spinocerebellar ataxia type 31 (SCA31) who had dystonia. He was referred to our hospital for evaluation following a 6-year history of slowly progressive unsteadiness of his left leg during walking and dysarthria at the age of 62 years old. On the basis of his symptoms, we diagnosed him as spinocerebellar degeneration (SCD), and prescribed taltirelin hydrate. However, his symptoms continued to worsen. He required a cane for walking at the age of 63 years, and a wheelchair at the age of 66 years. He was admitted to our hospital following acute cerebral infarction at the age of 77 years. On examination at admission, right hemiparesis and cerebellar ataxia were detected. And left hallux moved involuntarily toward the top surface of the foot at rest, that is dystonia. The dystonia was not associated with cerebral infarction, because it had been several years with dystonia that he got cerebral infarction. Genetic analysis revealed that this patient harbored a heterozygous SCA31 mutation. Previously there have been no reports of SCA31 associated with dystonia. Our case report support clinical heterogeneity of SCA31, and highlight the importance of considering this type in patients with dystonia and ataxia. Patients with the combination of dystonia and ataxia and a family history of a neurodegenerative disorder should be tested for SCA31.

Genetic variation of NEDD4L has been associated with hypertension and related phenotypes with conflicting results, probably attributable to gender-, age- and ethnicity-related variations in its phenotypic expression. We evaluated the association of three representative polymorphisms in NEDD4L (rs2288774, rs3865418 and rs4149601) with essential hypertension (EH) in a community-based sample of men (n = 1029) and women (n = 869) belonging to Han Chinese, Southern China, to probe whether gender interacts with NEDD4L in contributing to the risk of EH. In this population sample, rs4149601 was excluded from further analysis due to deviation from Hardy-Weinberg equilibrium. For two other variants tested, the allele frequencies and genotype distributions did not differ between cases and controls (p > 0.05) when both genders were combined. However, sex-stratified analysis revealed that the distribution of the dominant model of rs2288774 (TC + CC versus TT) and the additive and dominant (CT + TT versus CC) models of rs3865418 differed significantly between cases and controls in men (p = 0.044, 0.041 and 0.016, respectively) but not in women. After adjusting for confounding factors, logistic regression analysis showed that rs2288774 and rs3865418 (in the dominant model) were still significantly associated with EH (rs2288774: OR = 0.73, 95% CI = 0.57-0.95, p = 0.017 and rs3865418: OR = 0.71, 95% CI = 0.55-0.92, p = 0.009) in men. There was a significant interaction between the NEDD4L genotype and gender (p for interaction: 0.046 for rs2288774 and 0.033 for rs3865418). Genetic variation in NEDD4L may have sex-dependent effects in the development of EH in Han Chinese. Previous studies that ignore gender-specific effects in their design and interpretation could have failed to identify a uniform conclusion.

BACKGROUND: Hypertension affects > 18.8% of adults in China. Indeed, hypertension is the most prevalent risk factor for cardiovascular morbidity and mortality worldwide. Genetic variation is thought to contribute to the etiology of hypertension. NEDD4L is a candidate gene for hypertension, both functionally and genetically. The purpose of the current study was to investigate the relationship between the variation in NEDD4L and essential hypertension in Kazakh, which is a relatively isolated population with a pure genetic background and is an ideal population to study genetic mechanisms of hypertension.
METHODS: We screened the promoter and exons of NEDD4L in 94 Kazakh hypertensive individuals to identify representative variations. Then, by genotyping the representative variations in the Kazakh general population, a case-control study was conducted.
RESULTS: By systemically screening variations of NEDD4L, we did not identify any functional mutations in NEDD4L. A new common variation (296921-296923delTTG), which is not found in the NCBI database, was identified. Three representative variations (296921-296923delTTG, rs2288774, and rs2288775) were successfully genotyped in the Kazakh general population. The distribution of the dominant model (AA vs. AG+GG) of rs2288775, the additive model, and the recessive model (II+ID vs. DD) of 296921-296923delTTG differed significantly between the cases and controls in females (P = 0.040, P = 0.024, and P = 0.007, respectively). After adjusting for confounding factors, logistic regression analysis showed that rs2288775 (in the dominant model) and 296921-296923delTTG (in the recessive model) were significantly associated with hypertension (rs2288775: OR = 1.479, 95% CI = 1.011-2.064, p = 0.044; and 296921-296923delTTG: OR = 1.908, 95% CI = 1.020-3.568, p = 0.043) in females. The frequency of the D-C-G haplotype was significantly higher for cases than for controls in females (P = 0.020). There was a significant interaction between the NEDD4L genotype and gender (P for interaction: 0.045 for rs2288775 and 0.064 for 296921-296923delTTG), but there was no significant interaction between the NEDD4L genotype and smoking (P for interaction: 0.616 for rs2288775 and 0.447 for 296921-296923delTTG). For females and total participants, the urinary Na excretion rate was significantly lower in the DD than the I/I+I/D individuals (P = 0.032 and P = 0.027 respectively).
CONCLUSIONS: The genetic variations of NEDD4L may be associated with essential hypertension in females in the Kazakh general population.

Neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) gene may play an important role in the development of hypertension by regulating the amiloride-sensitive epithelial sodium channel for sodium reabsorption. Recently, a functional polymorphism located at the last nucleotide of exon 1 (rs4149601) of the NEDD4L gene were found to be associated with hypertension both in African Americans and whites, and a \"flip-flop\" association with hypertension was found in two white samples for a polymorphism located at intron 13 (rs3865418). In this study, we aimed at examining the role of these two variants on essential hypertension in Chinese Hans. In a population-based association study, we observed significantly higher prevalence of T allelic frequencies (p = 0.023) in hypertensives than normotensives. In logistic regression analysis, the stronger association was found under the additive model with an odds ratio of 1.31 (1.04-1.67) for T allele (p = 0.025). The association remained significant (p = 0.039) with an odds ratio of 1.29 (1.01-3.66) when adjusting for age and sex. We also constructed an ANCOVA factorial model by using clinical parameters as the dependent variable for rs3865418 polymorphisms. A significantly higher diastolic blood pressure was observed at rs3865418 in the dominant model for the T allele (p = 0.009). The positive association still exist after controlling age and sex (p = 0.013). For rs4149601 polymorphism, however, we did not observe a positive association with hypertension by implicating either logistic regression models or ANCOVA models. Thus, our results support rs3865418 but not rs4149601 polymorphism of NEDD4L gene implicated in the prevalence of hypertension in Chinese Hans.