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De novo mutation in KITLG gene causes a variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH).

ABSTRACT: Familial Progressive Hyper- and Hypopigmentation is a pigmentary disorder characterized by a mix of hypo- and hyperpigmented lesions, café-au-lait spots and hypopigmented ash-leaf macules. The disorder was previously linked to KITLG and various mutations have been reported to segregate in different families. Furthermore, association between KITLG mutations and malignancies was also suggested. Exome and SANGER sequencing were performed for identification of KITLG mutations. Functional in silico analyses were additionally performed to assess the findings. We identified a de novo mutation in exon 4 of KITLG gene causing NM_000899.4:c.[329A>T] (chr12:88912508A>T) leading to NP_000890.1:p.(Asp110Val) substitution in the 3rd alpha helix. It was predicted as pathogenic, located in a conserved region and causing an increase in hydrophobicity in the KITLG protein. Our findings clearly confirm an additional hot spot of KITLG mutations in the 3rd alpha helix, which very likely increases the risk of malignancies. To our knowledge the present study provides the strongest evidence of association of the KITLG mutation with both Familial Progressive Hyper- and Hypopigmentation and malignancy due to its' location on somatic cancer mutation locus. Additionally we also address difficulties with classification of the unique phenotype and propose a subtype within broader diagnosis.

SUBMITTER: Gorenjak M

PROVIDER: S-EPMC8683634 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Identification of a novel mutation in the KITLG gene in a Chinese family with familial progressive hyper- and hypopigmentation.

Project description:BackgroundFamilial progressive hyper- and hypopigmentation (FPHH, MIM 145250) is a rare hereditary skin disorder that is predominantly characterized by progressive, diffuse, partly blotchy hyperpigmented lesions intermingled with scattered hypopigmented spots, lentigines and sometimes Cafe-au-lait spots (CALs). Heterozygous mutations of the KIT ligand (KITLG, MIM 184745) gene are responsible for FPHH. To date, only eight KITLG mutations have been reported to be associated with FPHH, and no clear genotype-phenotype correlations have been established. This study aimed to identify the causative mutations in the KITLG gene in two Chinese FPHH patients.MethodsDirect sequencing of the coding regions of KITLG was performed. Pathogenicity prediction was performed using bioinformatics tools, including SIFT, Polyphen2, and SWISS-MODEL, and the results were further evaluated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsThe novel mutation c.104A?>?T (p.Asn35Ile) and the recurrent mutation c.101C?>?T (p.Thr34Ile) in KITLG were identified. As shown using SIFT and Polyphen-2 software, both mutations identified in this study were predicted to be detrimental variations. Three-dimensional protein structure modeling indicated that the mutant KITLG proteins might affect the affinity of KITLG for its receptor, c-KIT. According to the 2015 ACMG guidelines, the novel mutation c.104A?>?T was 'likely pathogenic'.ConclusionsTo date, most of the identified KITLG mutations have been clustered within the conserved VTNNV motif (amino acids 33-37) in exon 2. The known mutations are only involved in 33 V, 34 T, 36 N, and 37 V but not 35 N. We have now identified a novel mutation in KITLG, c.104A?>?T, that was first reported in FPHH within the conserved 35 N motif. These results strengthen our understanding of FPHH and expand the mutational spectrum of the KITLG gene.

| S-EPMC7789533 | biostudies-literature

A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.

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| S-EPMC8684165 | biostudies-literature

A novel de novo intronic variant in ITPR1 causes Gillespie syndrome.

Project description:Gillespie syndrome (GLSP) is characterized by bilateral symmetric partial aplasia of the iris presenting as a fixed and large pupil, cerebellar hypoplasia with ataxia, congenital hypotonia, and varying levels of intellectual disability. GLSP is caused by either biallelic or heterozygous, dominant-negative, pathogenic variants in ITPR1. Here, we present a 5-year-old male with GLSP who was found to have a heterozygous, de novo intronic variant in ITPR1 (NM_001168272.1:c.5935-17G > A) through genome sequencing (GS). Sanger sequencing of cDNA from this individual's fibroblasts showed the retention of 15 nucleotides from intron 45, which is predicted to cause an in-frame insertion of five amino acids near the C-terminal transmembrane domain of ITPR1. In addition, qPCR and cDNA sequencing demonstrated reduced expression of both ITPR1 alleles in fibroblasts when compared to parental samples. Given the close proximity of the predicted in-frame amino acid insertion to the site of previously described heterozygous, de novo, dominant-negative, pathogenic variants in GLSP, we predict that this variant also has a dominant-negative effect on ITPR1 channel function. Overall, this is the first report of a de novo intronic variant causing GLSP, which emphasizes the utility of GS and cDNA studies for diagnosing patients with a clinical presentation of GLSP and negative clinical exome sequencing.

| S-EPMC8562426 | biostudies-literature

A novel, de novo intronic variant in POGZ causes White-Sutton syndrome.

Project description:White-Sutton syndrome (WHSUS), which is caused by heterozygous pathogenic variants in POGZ, is characterized by a spectrum of intellectual disabilities and global developmental delay with or without features of autism spectrum disorder. Additional features may include hypotonia, behavioral abnormalities, ophthalmic abnormalities, hearing loss, sleep apnea, microcephaly, dysmorphic facial features, and rarely, congenital diaphragmatic hernia (CDH). We present a 6-year-old female with features of WHSUS, including CDH, but with nondiagnostic clinical trio exome sequencing. Exome sequencing reanalysis revealed a heterozygous, de novo, intronic variant in POGZ (NM_015100.3:c.2546-20T>A). RNA sequencing revealed that this intronic variant leads to skipping of exon 18. This exon skipping event results in a frameshift with a predicted premature stop codon in the last exon and escape from nonsense-mediated mRNA decay (NMD). To our knowledge, this case is the first case of WHSUS caused by a de novo, intronic variant that is not near a canonical splice site within POGZ. These findings emphasize the limitations of standard clinical exome filtering algorithms and the importance of research reanalysis of exome data together with RNA sequencing to confirm a suspected diagnosis of WHSUS. As the sixth reported case of CDH with heterozygous pathogenic variants in POGZ and features consistent with WHSUS, this report supports the conclusion that WHSUS should be considered in the differential diagnosis for patients with syndromic CDH.

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A de novo germline mutation in MYH7 causes a progressive dominant myopathy in pigs.

Project description:BackgroundAbout 9% of the offspring of a clinically healthy Piétrain boar named 'Campus' showed a progressive postural tremor called Campus syndrome (CPS). Extensive backcross experiments suggested a dominant mode of inheritance, and the founder boar was believed to be a gonadal mosaic. A genome-scan mapped the disease-causing mutation to an 8 cM region of porcine chromosome 7 containing the MHY7 gene. Human distal myopathy type 1 (MPD1), a disease partially resembling CPS in pigs, has been associated with mutations in the MYH7 gene.ResultsThe porcine MYH7 gene structure was predicted based on porcine reference genome sequence, porcine mRNA, and in comparison to the human ortholog. The gene structure was highly conserved with the exception of the first exon. Mutation analysis of a contiguous genomic interval of more than 22 kb spanning the complete MYH7 gene revealed an in-frame insertion within exon 30 of MYH7 (c.4320_4321insCCCGCC) which was perfectly associated with the disease phenotype and confirmed the dominant inheritance. The mutation is predicted to insert two amino acids (p.Ala1440_Ala1441insProAla) in a very highly conserved region of the myosin tail. The boar 'Campus' was shown to be a germline and somatic mosaic as assessed by the presence of the mutant allele in seven different organs.ConclusionThis study illustrates the usefulness of recently established genomic resources in pigs. We have identified a spontaneous mutation in MYH7 as the causative mutation for CPS. This paper describes the first case of a disorder caused by a naturally occurring mutation in the MYH7 gene of a non-human mammalian species. Our study confirms the previous classification as a primary myopathy and provides a defined large animal model for human MPD1. We provide evidence that the CPS mutation occurred during the early development of the boar 'Campus'. Therefore, this study provides an example of germline mosaicism with an asymptomatic founder.

| S-EPMC3542579 | biostudies-literature

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Project description:We report an 8-year-old boy with a complex cerebral malformation, intellectual disability, and complex partial seizures. Whole-exome sequencing revealed a yet unreported de novo variant in the PIK3R2 gene that was recently associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome and bilateral perisylvian polymicrogyria (BPP). Our patient showed cerebral abnormalities (megalencephaly, perisylvian polymicrogyria, and mega corpus callosum) that were consistent with these conditions. Imaging also showed right temporal anomalies suggestive of cortical dysplasia. Until now, only three variants (c.1117G>A (p.(G373R)), c.1126A>G (p.(K376E)) and c.1202T>C (p.(L401P))) affecting the SH2 domain of the PIK3R2 protein have been reported in MPPH and BPP syndromes. In contrast to the variants reported so far, the patient described herein exhibits the c.1669G>C (p.(D557H)) variant that affects a highly conserved residue at the interface with the PI3K catalytic subunit ?. The phenotypic spectrum associated with variants in this gene and its pathway are likely to continue to expand as more cases are identified.

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Project description: Not available

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Project description:The GABRA1 gene encodes one of the most conserved and highly expressed subunits of the GABAA receptor family. Variants in this gene are causatively implicated in different forms of epilepsy and also more severe epilepsy-related neurodevelopmental syndromes. Here we study functional consequences of a novel de novo missense GABRA1 variant, p.(Ala332Val), identified through exome sequencing in an individual affected by early-onset syndromic epileptic encephalopathy. The variant is localised within the transmembrane domain helix 3 (TM3) and in silico prediction algorithms suggested this variant to be likely pathogenic. In vitro assessment revealed unchanged protein levels, regular assembly and forward trafficking to the cell surface. On the functional level a significant left shift of the apparent GABA potency in two-electrode voltage clamp electrophysiology experiments was observed, as well as changes in the extent of desensitization. Additionally, apparent diazepam potency was left shifted in radioligand displacement assays. During prenatal development mainly alpha2/3 subunits are expressed, whereas after birth a switch to alpha1 occurs. The expression of alpha1 in humans is upregulated during the first years. Thus, the molecular change of function reported here supports pathogenicity and could explain early-onset of seizures in the affected individual.

| S-EPMC7012862 | biostudies-literature

De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity.

Project description:Epilepsy is one of the most common neurological diseases and it causes profound morbidity and mortality. We identified the first de novo variant in KCNMA1 (c.2984?A?>?G (p.(N995S)))-encoding the BK channel-that causes epilepsy, but not paroxysmal dyskinesia, in two independent families. The c.2984?A?>?G (p.(N995S)) variant markedly increased the macroscopic potassium current by increasing both the channel open probability and channel open dwell time. The c.2984?A?>?G (p.(N995S)) variant did not affect the calcium sensitivity of the channel. We also identified three other variants of unknown significance (c.1554?G?>?T (p.(K518N)), c.1967A?>?C (p.(E656A)), and c.3476?A?>?G (p.(N1159S))) in three separate patients with divergent epileptic phenotypes. However, these variants did not affect the BK potassium current, and are therefore unlikely to be disease-causing. These results demonstrate that BK channel variants can cause epilepsy without paroxysmal dyskinesia. The underlying molecular mechanism can be increased activation of the BK channel by increased sensitivity to the voltage-dependent activation without affecting the sensitivity to the calcium-dependent activation. Our data suggest that the BK channel may represent a drug target for the treatment of epilepsy. Our data highlight the importance of functional electrophysiological studies of BK channel variants in distinguishing whether a genomic variant of unknown significance is a disease-causing variant or a benign variant.

| S-EPMC5839055 | biostudies-literature

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