ABSTRACT
INTRODUCTION: Piebaldism is a rare autosomal dominant disorder characterized by congenital white forelock and depigmented patches, which is most commonly caused by deleterious variants in the KIT gene. METHODS: Four KIT variants were identified in a piebaldism case series by whole-exome sequencing. Functional experiments, including in vitro minigene reporter assay and enzyme-linked immunosorbent assay, were carried out to elucidate the pathogenicity of the variants. The genotype-phenotype correlation was summarized through extensive literature reviewing. RESULTS: All the four cases had severe piebaldism presented with typical white forelock and diffuse depigmentation on the ventral trunk and limbs. Four germline variants at the tyrosine kinase (TK) domains of the KIT gene were identified: two novel variants c.1990+1G>A (p.Pro627_Gly664delinsArg) and c.2716T>C (p.Cys906Arg), and two known variants c.1879+1G>A (p.Gly592_Pro627delinsAla) and c.1747G>A (p.Glu583Lys). Both splicing variants caused exon skipping and inframe deletions in the TK1 domain. The missense variants resided at the TK1 and TK2 domains respectively impairing PI3K/AKT and MAPK/ERK signaling pathways, the downstream of KIT. All severe cases were associated with variants in the TK domains, eliciting a major dominant-negative mechanism of the disease. CONCLUSION: Our data expand the mutation spectrum of KIT, emphasized by a dominant-negative effect of variants in the critical TK domains in severe cases. We also share the experience of prenatal diagnosis and informed reproductive choices for the affected families.
Subject(s)
Germ-Line Mutation , Piebaldism , Proto-Oncogene Proteins c-kit , Female , Humans , Infant , Male , Exome Sequencing , Pedigree , Piebaldism/genetics , Proto-Oncogene Proteins c-kit/geneticsABSTRACT
INTRODUCTION: Piebaldism is the dominantly inherited skin disorder clinically characterized by congenital stable and well circumscribed patches of leukoderma (depigmented skin) of ventral distribution, involving central forehead, frontal chest and abdomen and central portion of limbs, and by localized poliosis (white hair). Inherited or de novo mutations in proto-oncogene KIT, encoding the transmembrane tyrosine kinase receptor c-kit, underly the majority of piebaldism cases. Piebaldism is a disorder characterized by incomplete penetrance and variable expressivity.
Subject(s)
Piebaldism , Humans , Piebaldism/genetics , Proto-Oncogene Proteins c-kit/genetics , Cafe-au-Lait Spots/geneticsABSTRACT
BACKGROUND: Piebaldism is a rare, autosomal dominant, and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SLUG genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder. METHODS: In this paper, we report a case of piebaldism with café-au-lait macules resulting from a novel mutation of KIT gene c.1982C > T (p.Thr661Ile) in a three-generation Chinese family. The whole-exome sequencing, mitochondrial gene 3000X, and bioinformatics tools were used to identify the mutation in this new-found pedigree. In addition, we searched the databases of "Punmed, Chinese National Knowledge Infrastructure, CMJD, WANFANG MED ONLINE", reviewed 88 cases of piebaldism caused by KIT gene mutation, and summarized the relationship between clinical phenotype and genotype of piebaldism through logistic regression and other statistical methods. RESULTS: The proband and her affected mother carried a heterozygous c.1982C > T missense mutation (p.Thr661Ile) on KIT gene. Bioinformatics analysis hinted that it had potential pathogenicity. The data showed that piebaldism patients with cafè-au-lait macules had KIT mutations almost located in the intracellular tyrosine kinase domain and were mostly related to the severe clinical phenotype of piebaldism. CONCLUSION: The new heterozygous c.1982C > T missense mutation on KIT caused piebaldism with café-au-lait macules in this Chinese family. This study provides a new reference index for clinicians to judge the severity of clinical phenotypes of piebaldism, broadens the understanding of the correlation between clinical phenotypes and genotypes of piebaldism, and provides reference of genetic counseling and prenatal diagnosis for affected families.
Subject(s)
Piebaldism , Pigmentation Disorders , Humans , Female , Piebaldism/genetics , Proto-Oncogene Proteins c-kit/genetics , Cafe-au-Lait Spots/diagnosis , Cafe-au-Lait Spots/genetics , Mutation/geneticsABSTRACT
Griscelli syndrome type 1 (GS1) is a rare inherited autosomal recessive disease caused by a deleterious variant in the MYO5A gene and characterized by general hypopigmentation, neurological symptoms, motor disability, hypotonia, and vision abnormality. Only nine pathogenic variants in the MYO5A gene have been confirmed in association with the GS1. All of the reported pathogenic variants are truncating. Herein, two siblings from a consanguineous Iranian family with abnormal pigmentation and neurological symptoms were referred for genetic counseling. Whole-exome sequencing (WES) revealed a novel homozygous truncating variant c.1633_1634delAA (p.Asn545Glnfs*10) in the MYO5A gene, which was completely co-segregated with the phenotype in all affected and unaffected family members. Computational analysis and protein modeling demonstrated the deleterious effects of this variant on the structure and function of the protein. The variant, according to ACMG guidelines, was classified as pathogenic. Besides the novelty of the identified variant, our patients manifested more severe clinical symptoms and presented distal hyperlaxity in all four limbs, which was a new finding. In conclusion, we expanded the mutational and phenotypic spectrum of the GS1. Moreover, by studying clinical manifestations in all molecularly confirmed reported cases, provided a comprehensive overview of clinical presentation, and attempted to find a genotype-phenotype correlation.
Subject(s)
Disabled Persons , Motor Disorders , Piebaldism , Humans , Iran , Piebaldism/genetics , Mutation , PedigreeABSTRACT
KIT is a type 3 receptor tyrosine kinase that plays a crucial role in cellular growth and proliferation. Mutations in KIT can dysregulate its active-inactive equilibrium. Activating mutations drive cancer growth, while deactivating mutations result in the loss of skin and hair pigmentation in a disease known as piebaldism. Here, we propose a method based on molecular dynamics and free energy calculations to predict the functional effect of KIT mutations. Our calculations may have important clinical implications by defining the functional significance of previously uncharacterized KIT mutations and guiding targeted therapy.
Subject(s)
Piebaldism , Proto-Oncogene Proteins c-kit , Humans , Mutation , Piebaldism/genetics , Proto-Oncogene Mas , Proto-Oncogene Proteins c-kit/geneticsSubject(s)
Piebaldism/genetics , Proto-Oncogene Proteins c-kit/genetics , Sequence Deletion , Asian People/genetics , Female , Humans , Infant , PedigreeABSTRACT
A 1-month-old, female, smooth-haired miniature Dachshund with dilute color and neurological defects was investigated. The aim of this study was to characterize the clinical signs, histopathological changes and underlying genetic defect. The puppy had visible coat color dilution and was unable to hold its head on its own or to remain in a stable prone position for an extended period. Histopathological examination revealed an accumulation of clumped melanin and deposition of accumulated keratin within the hair follicles, accompanied by dermal pigmentary incontinence. These dermatological changes were compatible with the histopathology described in dogs with an MLPH-related dilute coat color. We sequenced the genome of the affected dog and compared the data to 795 control genomes. MYO5A, coding for myosin VA, was investigated as the top functional candidate gene. This search revealed a private homozygous frameshift variant in MYO5A, XM_022412522.1:c.4973_4974insA, predicted to truncate 269 amino acids (13.8%) of the wild type myosin VA protein, XP_022268230.1:p.(Asn1658Lysfs*28). The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 142 additionally genotyped, unrelated Dachshund dogs. MYO5A loss of function variants cause Griscelli type 1 syndrome in humans, lavender foal in horses and the phenotype of the dilute mouse mutant. Based on the available data, together with current knowledge on other species, we propose the identified MYO5A frameshift insertion as a candidate causative variant for the observed dermatological and neurological signs in the investigated dog.
Subject(s)
Dog Diseases/genetics , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/genetics , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Piebaldism/genetics , Pigmentation Disorders/genetics , Alleles , Animals , Dog Diseases/pathology , Dogs , Frameshift Mutation/genetics , Genotype , Hair Color/genetics , Hearing Loss, Sensorineural/pathology , Homozygote , Humans , Phenotype , Piebaldism/pathology , Pigmentation/genetics , Pigmentation Disorders/pathologyABSTRACT
BACKGROUND: Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disease caused by mutations in RAB27A gene. It is primarily characterized by a combination of partial albinism, hemophagocytic lymphohistiocytosis (HLH) or other immunodeficiency. However, neurological involvement at onset in GS2 and treatment has rarely been described. CASE PRESENTATION: We describe a 3-year-old boy with GS2 in an Asian Chinese family. He presented with progressive neurological abnormalities following unremitting fever at onset. He developed HLH during the clinical course. A novel homozygous mutation (c.1 A > G) in RAB27A gene was subsequently identified. He was then treated by HLH-1994 protocol combined with ruxolitinib and experienced a dramatic remission. He subsequently underwent a successful haploidentical hematopoietic stem cell transplantation and stayed at a good condition. CONCLUSIONS: We reported an atypical form of GS2 manifesting as severe central nervous system involvement at onset and subsequent HLH, which was successfully rescued in time. This case also highlights the need for early consideration of immunologic and genetic evaluation for HLH in unexplained neuroinflammation in the diagnostic work up.
Subject(s)
Lymphohistiocytosis, Hemophagocytic , Piebaldism , Primary Immunodeficiency Diseases , Child, Preschool , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/therapy , Male , Piebaldism/complications , Piebaldism/diagnosis , Piebaldism/genetics , rab27 GTP-Binding Proteins/geneticsSubject(s)
Adaptor Protein Complex 3/genetics , Adaptor Protein Complex beta Subunits/genetics , Hermanski-Pudlak Syndrome/genetics , Hermanski-Pudlak Syndrome/pathology , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/pathology , Piebaldism/genetics , Piebaldism/pathology , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/pathology , Adolescent , Child , Female , Gene Deletion , Hermanski-Pudlak Syndrome/immunology , Humans , Lymphohistiocytosis, Hemophagocytic/immunology , Male , Piebaldism/immunology , Primary Immunodeficiency Diseases/immunologyABSTRACT
Griscelli syndrome type 2 is a rare autosomal recessive disorder characterized by hypopigmentation, silvery hair, and immunological dysfunction with no primary neurological impairment. We report an 18-month-old girl with Griscelli syndrome type 2 who presented to the dermatology department for cutaneous granulomas that developed following live-attenuated vaccination. Two compound heterozygous variants in the RAB27A gene were subsequently identified. She developed hemophagocytic lymphohistiocytosis, the key immunological concern, at age 5 years.
Subject(s)
Immunologic Deficiency Syndromes , Lymphohistiocytosis, Hemophagocytic , Piebaldism , Child, Preschool , Female , Granuloma/diagnosis , Granuloma/etiology , Humans , Infant , Lymphohistiocytosis, Hemophagocytic/diagnosis , Piebaldism/diagnosis , Piebaldism/genetics , Primary Immunodeficiency DiseasesSubject(s)
Piebaldism , Humans , Japan , Mutation , Pedigree , Piebaldism/diagnosis , Piebaldism/genetics , Proto-Oncogene Proteins c-kit/geneticsABSTRACT
Griscelli syndrome type 2 (GS-2) is an inborn error of immunity characterized by partial albinism and episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by RAB27A mutations that encode RAB27A, a member of the Rab GTPase family. RAB27A is expressed in many tissues and regulates vesicular transport and organelle dynamics. Occasionally, GS-2 patients with RAB27A mutation display normal pigmentation. The study of such variants provides the opportunity to map distinct binding sites for tissue-specific effectors on RAB27A. Here we present a new case of GS-2 without albinism (GS-2 sine albinism) caused by a novel missense mutation (Val143Ala) in the RAB27A and characterize its functional cellular consequences. Using pertinent animal cell lines, the Val143Ala mutation impairs both the RAB27A-SLP2-A interaction and RAB27A-MUNC13-4 interaction, but it does not affect the RAB27A-melanophilin (MLPH)/SLAC2-A interaction that is crucial for skin and hair pigmentation. We conclude that disruption of the RAB27A-MUNC13-4 interaction in cytotoxic lymphocytes leads to the HLH predisposition of the GS-2 patient with the Val143Ala mutation. Finally, we include a review of GS-2 sine albinism cases reported in the literature, summarizing their genetic and clinical characteristics.
Subject(s)
Albinism/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , Piebaldism/genetics , Primary Immunodeficiency Diseases/genetics , rab27 GTP-Binding Proteins/genetics , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Animals , Binding Sites/genetics , COS Cells , Cell Line , Child , Child, Preschool , Chlorocebus aethiops , Female , Humans , Infant , Infant, Newborn , Leukocytes, Mononuclear/metabolism , Male , Membrane Proteins/genetics , Mutation, Missense/genetics , rab GTP-Binding Proteins/geneticsABSTRACT
Piebaldism is a rare, autosomal dominant disorder characterized by the congenital absence of melanocytes in affected areas of the skin and hair. We report on a familial 4q12 deletion that involves the KIT gene and causes piebaldism in affected individuals. Whole-genome genotyping analysis of the proband using HumanCytoSNP-12v2.1 BeadChips (Illumina Inc., San Diego, CA, USA, revealed a 1.34-Mb microduplication of 1q21.1q21.2 and a 2.7-Mb microdeletion of 4q12. The analysis of the parents confirmed the paternal origin of the 4q12 microdeletion. The clinical and molecular findings in the proband and his affected relatives showed that the 2.7-Mb 4q12 microdeletion, the smallest microdeletion reported to date, causes isolated piebaldism due to the loss of the KIT gene.
Subject(s)
Piebaldism/genetics , Proto-Oncogene Proteins c-kit/genetics , Child , Female , Gene Deletion , Genotype , Humans , Male , PedigreeABSTRACT
Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic variants in the RAB27A gene and characterized by partial albinism, immunodeficiency, and occasional hematological and neurological involvement. We reviewed and analyzed the medical records of 12 individuals with GS2 from six families belonging to a highly consanguineous Qatari tribe and with a recurrent pathogenic variant in the RAB27A gene (NM_004580.4: c.244C > T, p.Arg82Cys). Detailed demographic, clinical, and molecular data were collected. Cutaneous manifestations were the most common presentation (42%), followed by neurological abnormalities (33%) and immunodeficiency (25%). The most severe manifestation was HLH (33%). Among the 12 patients, three patients (25%) underwent HSCT, and four (33%) died. The cause of death in all four patients was deemed HLH, providing evidence for this complication's fatal nature. Interestingly, two affected patients (16%) were asymptomatic. This report highlights the broad spectrum of clinical presentations of GS2 associated with a founder variant in the RAB27A gene (c.244C > T, p.Arg82Cys). Early suspicion of GS2 among Qatari patients with cutaneous manifestations, neurological findings, immunodeficiency, and HLH would shorten the diagnostic odyssey, guide early and appropriate treatment, and prevent fatal outcomes.
Subject(s)
Founder Effect , Lymphohistiocytosis, Hemophagocytic/genetics , Phenotype , Piebaldism/genetics , Primary Immunodeficiency Diseases/genetics , rab27 GTP-Binding Proteins/genetics , Adolescent , Child , Child, Preschool , Exome , Family Health , Female , Homozygote , Humans , Infant , Male , Pedigree , Qatar , Recurrence , Young AdultSubject(s)
Lymphohistiocytosis, Hemophagocytic , Piebaldism , Primary Immunodeficiency Diseases , rab27 GTP-Binding Proteins/genetics , Adolescent , Autografts , Hematopoietic Stem Cell Transplantation , Humans , Lymphohistiocytosis, Hemophagocytic/diagnostic imaging , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Piebaldism/diagnostic imaging , Piebaldism/genetics , Piebaldism/pathology , Primary Immunodeficiency Diseases/diagnostic imaging , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/pathologySubject(s)
Hearing Loss, Sensorineural/genetics , Immunologic Deficiency Syndromes/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Nervous System Diseases/genetics , Piebaldism/genetics , Pigmentation Disorders/genetics , Child , Child, Preschool , Codon, Nonsense , Egypt/epidemiology , Female , Genotype , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/epidemiology , Hearing Loss, Sensorineural/pathology , Humans , Hypopigmentation/diagnosis , Hypopigmentation/etiology , Hypopigmentation/genetics , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/etiology , Infant , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Male , Nervous System Diseases/diagnosis , Nervous System Diseases/etiology , Pedigree , Phenotype , Piebaldism/diagnosis , Piebaldism/epidemiology , Piebaldism/pathology , Pigmentation Disorders/diagnosis , Pigmentation Disorders/epidemiology , Pigmentation Disorders/pathology , PrevalenceABSTRACT
Piebaldism is a rare, autosomal dominant and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SNAI2 genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder. Herein, we report a 5-month-old Chinese girl with severe piebaldism but no family history thereof. She has white forelock and large patches of depigmentation in the jaw, central anterior trunk, perineum and extremities. We performed whole-exome and Sanger sequencing and identified a de novo KIT mutation (NM_000222.2: c.2657G>A, p.Gly886Val) in exon 18 of KIT in the proband. Currently, this mutation is located in the most extreme C-terminal of the tyrosine kinase domain 2 of the KIT gene amongst all reported mutations and causes a severe clinical phenotype. We further reviewed literature on piebaldism and summarized 79 KIT gene mutations that lead to this disease. Our study may expand knowledge on the genotype-phenotype correlation in piebaldism and serve as a reference for genetic counseling and prenatal diagnosis of affected families.