RESUMO
Dilated cardiomyopathy (DCM) is defined as left ventricular enlargement accompanied by systolic dysfunction not explained by abnormal loading conditions or coronary heart disease. The DCM clinical spectrum is broad, ranging from subclinical to severe presentation with progression to end stage heart failure. To date, different genetic loci have been found to have moderate/definitive evidence for causality in DCM and pathogenic variants in the TTN gene represent the main genetic determinant. Here, we describe a family in which the co-occurrence of two genetic hits, one in the TTN and one in the BAG3 gene, was associated with heterogeneous clinical presentation ranging from subclinical phenotypes to acute cardiogenic shock mimicking fulminant myocarditis. We hypothesize that at least some specific BAG3 genotypes could be related to DCM presenting with acute heart failure and suggest that patients and relatives carrying BAG3 pathogenic variants should be addressed to a tertiary-level heart care center.
RESUMO
PURPOSE: The SF3B splicing complex is composed of SF3B1-6 and PHF5A. We report a developmental disorder caused by de novo variants in PHF5A. METHODS: Clinical, genomic, and functional studies using subject-derived fibroblasts and a heterologous cellular system were performed. RESULTS: We studied 9 subjects with congenital malformations, including preauricular tags and hypospadias, growth abnormalities, and developmental delay who had de novo heterozygous PHF5A variants, including 4 loss-of-function (LOF), 3 missense, 1 splice, and 1 start-loss variant. In subject-derived fibroblasts with PHF5A LOF variants, wild-type and variant PHF5A mRNAs had a 1:1 ratio, and PHF5A mRNA levels were normal. Transcriptome sequencing revealed alternative promoter use and downregulated genes involved in cell-cycle regulation. Subject and control fibroblasts had similar amounts of PHF5A with the predicted wild-type molecular weight and of SF3B1-3 and SF3B6. SF3B complex formation was unaffected in 2 subject cell lines. CONCLUSION: Our data suggest the existence of feedback mechanisms in fibroblasts with PHF5A LOF variants to maintain normal levels of SF3B components. These compensatory mechanisms in subject fibroblasts with PHF5A or SF3B4 LOF variants suggest disturbed autoregulation of mutated splicing factor genes in specific cell types, that is, neural crest cells, during embryonic development rather than haploinsufficiency as pathomechanism.
Assuntos
Anormalidades Craniofaciais , Hipospadia , Masculino , Humanos , Hipospadia/genética , Fatores de Processamento de RNA/genética , Splicing de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transativadores/genética , Proteínas de Ligação a RNA/genéticaRESUMO
Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. We previously studied eleven healthy subjects from eight different families presenting with unexplained hyperferritinemia. Their findings suggested the existence of an autosomal-recessive disorder. We carried out whole-exome sequencing to detect the genetic cause of hyperferritinemia. Immunohistochemistry and flow cytometry assays were performed on liver biopsies and monocyte-macrophages to confirm the pathogenic role of the identified candidate variants. Through a combined approach of whole-exome sequencing and homozygosity mapping, we found bi-allelic STAB1 variants in ten subjects from seven families. STAB1 encodes the multifunctional scavenger receptor stabilin-1. Immunohistochemistry and flow cytometry analyses showed absent or markedly reduced stabilin-1 in liver samples, monocytes, and monocyte-derived macrophages. Our findings show a strong association between otherwise unexplained hyperferritinemia and bi-allelic STAB1 mutations suggesting the existence of another genetic cause of hyperferritinemia without iron overload and an unexpected function of stabilin-1 in ferritin metabolism.
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Hiperferritinemia , Sobrecarga de Ferro , Humanos , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/diagnóstico , Ferritinas/genética , Macrófagos , AlelosRESUMO
Deleterious variants in collagen genes are the most common cause of hereditary connective tissue disorders (HCTD). Adaptations of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria are still lacking. A multidisciplinary team was set up for developing specifications of the ACMG/AMP criteria for COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL11A1, COL11A2 and COL12A1, associated with various forms of HCTD featuring joint hypermobility, which is becoming one of the most common reasons of referral for molecular testing in this field. Such specifications were validated against 209 variants, and resulted effective for classifying as pathogenic and likely pathogenic null alleles without downgrading of the PVS1 level of strength and recurrent Glycine substitutions. Adaptations of selected criteria reduced uncertainties on private Glycine substitutions, intronic variants predicted to affect the splicing, and null alleles with a downgraded PVS1 level of strength. Segregation and multigene panel sequencing data mitigated uncertainties on non-Glycine substitutions by the attribution of one or more benignity criteria. These specifications may improve the clinical utility of molecular testing in HCTD by reducing the number of variants with neutral/conflicting interpretations. Close interactions between laboratory and clinicians are crucial to estimate the a priori utility of molecular test and to improve medical reports.
Assuntos
Variação Genética , Instabilidade Articular , Humanos , Estados Unidos , Testes Genéticos/métodos , Instabilidade Articular/diagnóstico , Instabilidade Articular/genética , Análise de Sequência de DNA/métodosRESUMO
Two adult siblings born to first-cousin parents presented a clinical phenotype reminiscent of Rothmund-Thomson syndrome (RTS), implying fragile hair, absent eyelashes/eyebrows, bilateral cataracts, mottled pigmentation, dental decay, hypogonadism, and osteoporosis. As the clinical suspicion was not supported by the sequencing of RECQL4, the RTS2-causative gene, whole exome sequencing was applied and disclosed the homozygous variants c.83G>A (p.Gly28Asp) and c.2624A>C (p.Glu875Ala) in the nucleoporin 98 (NUP98) gene. Though both variants affect highly conserved amino acids, the c.83G>A looked more intriguing due to its higher pathogenicity score and location of the replaced amino acid between phenylalanine-glycine (FG) repeats within the first NUP98 intrinsically disordered region. Molecular modeling studies of the mutated NUP98 FG domain evidenced a dispersion of the intramolecular cohesion elements and a more elongated conformational state compared to the wild type. This different dynamic behavior may affect the NUP98 functions as the minor plasticity of the mutated FG domain undermines its role as a multi-docking station for RNA and proteins, and the impaired folding can lead to the weakening or the loss of specific interactions. The clinical overlap of NUP98-mutated and RTS2/RTS1 patients, accounted by converging dysregulated gene networks, supports this first-described constitutional NUP98 disorder, expanding the well-known role of NUP98 in cancer.
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Mutação em Linhagem Germinativa , Complexo de Proteínas Formadoras de Poros Nucleares , Síndrome de Rothmund-Thomson , Humanos , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Síndrome de Rothmund-Thomson/genética , Irmãos , Masculino , Feminino , Conformação ProteicaRESUMO
Constitutional heterozygous mutations in CHEK2 gene have been associated with hereditary cancer risk. To date, only a few homozygous CHEK2 mutations have been reported in families with cancer susceptibility. Here, we report two unrelated individuals with a personal and familial cancer history in whom biallelic CHEK2 alterations were identified. The first case resulted homozygous for the CHEK2 c.793-1 G > A (p.Asp265Thrfs*10) variant, and the second one was found to be compound heterozygous for the c.1100delC (p.Thr367Metfs*15) and the c.1312 G > T (p.Asp438Tyr) variants. Multiple cytogenetic anomalies were demonstrated on peripheral lymphocytes of both patients. A literature revision showed that a single other CHEK2 homozygous variant was previously associated to a constitutional randomly occurring multi-translocation karyotype from peripheral blood in humans. We hypothesize that, at least some biallelic CHEK2 mutations might be associated with a novel disorder, further expanding the group of chromosome instability syndromes. Additional studies on larger cohorts are needed to confirm if chromosomal instability could represent a marker for CHEK2 constitutionally mutated recessive genotypes, and to investigate the cancer risk and the occurrence of other anomalies typically observed in chromosome instability syndromes.
Assuntos
Neoplasias da Mama , Proteínas Serina-Treonina Quinases , Humanos , Feminino , Proteínas Serina-Treonina Quinases/genética , Predisposição Genética para Doença , Quinase do Ponto de Checagem 2/genética , Mutação , Genótipo , Instabilidade CromossômicaRESUMO
In 2018, a new clinical subtype, caused by biallelic variants in the AEBP1 gene, encoding the ACLP protein, was added to the current nosological classification of the Ehlers-Danlos Syndromes (EDS). This new phenotype, provisionally termed EDS classical-like type 2 (clEDS2), has not yet been fully characterized, as only nine cases have been reported to date. Here we describe a patient, homozygous for a novel AEBP1 pathogenic variant (NM_001129.5 c.2123_2124delTG (p.Val708AlafsTer5)), whose phenotype is reminiscent of classical EDS but also includes previously unreported multiple congenital malformations. Furthermore, we briefly summarize the current principal clinical manifestations of clEDS2 and the molecular evidence surrounding the role of AEBP1 in the context of extracellular matrix homeostasis and connective tissue development. Although a different coexisting etiology for the multiple congenital malformations of our patient cannot be formally excluded, the emerging role of ACLP in TGF-ß and WNT pathways may explain their occurrence and the phenotypical variability of clEDS2.
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Síndrome de Ehlers-Danlos , Humanos , Mutação , Síndrome de Ehlers-Danlos/patologia , Matriz Extracelular/genética , Fenótipo , Homozigoto , Carboxipeptidases/genética , Proteínas Repressoras/genéticaRESUMO
X-linked intellectual disability can be diagnosed in about 10-12% of intellectually disabled males. In the past, mutations affecting the PAK3 gene (p21 protein-activated kinase 3, MIM#300142) have been associated with a non-syndromic form of X-linked intellectual disability, which has to date been identified in a limited number of families.Since this neurodevelopmental disorder mostly afflicts males, descriptions of symptomatic female carriers are quite rare.We describe a female patient with neurodevelopmental delay and a novel PAK3 variant. Interestingly, she manifests craniofacial anomalies, including microcephaly, representing the second reported microcephalic female but the first for whom a detailed clinical description is available. She also displays other uncommon clinical findings, which we illustrate.Moreover, a comprehensive clinical and molecular review of all to date published patients has been made. This study contributes to further delineate the PAK3-related phenotype, which can be considered a non-syndromic X-linked intellectual disability, with seemingly recurrent craniofacial abnormalities.
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Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Microcefalia/genética , Fenótipo , Quinases Ativadas por p21/genética , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Deficiência Intelectual/patologia , Microcefalia/patologia , Mutação , Quinases Ativadas por p21/metabolismoRESUMO
Biallelic pathogenic variants in POC1A result in SOFT (Short-stature, Onychodysplasia, Facial-dysmorphism, and hypoTrichosis) and variant POC1A-related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype-phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT-PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.
Assuntos
Proteínas de Ciclo Celular/genética , Hiperinsulinismo Congênito/genética , Proteínas do Citoesqueleto/genética , Dislipidemias/genética , Acantose Nigricans/genética , Adulto , Idade de Início , Proteínas de Ciclo Celular/deficiência , Simulação por Computador , Hiperinsulinismo Congênito/tratamento farmacológico , Proteínas do Citoesqueleto/deficiência , DNA Complementar/genética , Dislipidemias/tratamento farmacológico , Éxons/genética , Ácidos Graxos Insaturados/uso terapêutico , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Resistência à Insulina , Metformina/uso terapêutico , Pessoa de Meia-Idade , Linhagem , Fenótipo , Plasmaferese , Isoformas de Proteínas/genética , Síndrome , Transcrição GênicaRESUMO
BACKGROUND: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. CMM pathogenesis involves genetic and environmental factors. Recent studies have led to the identification of new genes involved in CMM susceptibility: beyond CDKN2A and CDK4, BAP1, POT1, and MITF were recently identified as potential high-risk melanoma susceptibility genes. OBJECTIVE: This study is aimed to evaluate the genetic predisposition to CMM in patients from central Italy. METHODS: From 1998 to 2017, genetic testing was performed in 888 cases with multiple primary melanoma and/or familial melanoma. Genetic analyses included the sequencing CDKN2A, CDK4, BAP1, POT1, and MITF in 202 cases, and of only CDKN2A and CDK4 codon 24 in 686 patients. By the evaluation of the personal and familial history, patients were divided in two clinical categories: "low significance" and "high significance" cases. RESULTS: 128 patients (72% belonging to the "high significance" category, 28% belonging to the "low significance" category) were found to carry a DNA change defined as pathogenic, likely pathogenic, variant of unknown significance (VUS)-favoring pathogenic or VUS. CONCLUSIONS: It is important to verify the genetic predisposition in CMM patients for an early diagnosis of further melanomas and/or other tumors associated with the characterized genotype.
Assuntos
Predisposição Genética para Doença/genética , Melanoma/genética , Melanoma/metabolismo , Adulto , Idoso , Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Humanos , Itália , Masculino , Fator de Transcrição Associado à Microftalmia/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Complexo Shelterina , Proteínas de Ligação a Telômeros/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
A rare developmental delay (DD)/intellectual disability (ID) syndrome with craniofacial dysmorphisms and autistic features, termed White-Sutton syndrome (WHSUS, MIM#614787), has been recently described, identifying truncating mutations in the chromatin regulator POGZ (KIAA0461, MIM#614787). We describe a further WHSUS patient harboring a novel nonsense de novo POGZ variant, which afflicts a protein domain with transposase activity less frequently impacted by mutational events (DDE domain). This patient displays additional physical and behavioral features, these latter mimicking Smith-Magenis syndrome (SMS, MIM#182290). Considering sleep-wake cycle anomalies and abnormal behavior manifested by this boy, we reinforced the clinical resemblance between WHSUS and SMS, being both chromatinopathies. In addition, using the DeepGestalt technology, we identified a different facial overlap between WHSUS patients with mutations in the DDE domain (Group 1) and individuals harboring variants in other protein domains/regions (Group 2). This report further delineates the clinical and molecular repertoire of the POGZ-related phenotype, adding a novel patient with uncommon clinical and behavioral features and provides the first computer-aided facial study of WHSUS patients.
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Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Síndrome de Smith-Magenis/genética , Transposases/genética , Pré-Escolar , Códon sem Sentido/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação/genética , Fenótipo , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/diagnóstico por imagem , Síndrome de Smith-Magenis/fisiopatologiaRESUMO
We describe the second patient with the de novo p.Arg377Trp variant in ACTL6A (Actin-like 6A) (MIM#604958) and a phenotype reminiscent a disorder of the BRG1-associated factor (BAF) complex, including dysmorphic facies and acral malformations. So far, only three patients with ACTL6A variants and neurodevelopmental delay have been reported but the specific p.Arg377Trp mutation seems to correlate with a distinctive phenotype well-fitting a BAFopathy, which lacks in individuals carrying different mutations. This could suggest an emergent genotype-phenotype correlation among the ACTL6A-related phenotype.
Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Deformidades Congênitas da Mão/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/patologia , Criança , Deformidades Congênitas da Mão/patologia , Humanos , Masculino , Micrognatismo/patologia , Transtornos do Neurodesenvolvimento/patologiaRESUMO
Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-ß pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.
Assuntos
Síndrome de Loeys-Dietz/genética , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Síndrome de Loeys-Dietz/classificação , Síndrome de Loeys-Dietz/patologia , Pessoa de Meia-Idade , Linhagem , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta2/genéticaRESUMO
Genetic syndromes are frequently associated with Intellectual Disability (ID), as well as craniofacial dysmorphisms. A group of ID syndromes with typical abnormal face related to chromatin remodeling defects, have been recognized, coining the term chromatinopathies. This is a molecular heterogeneous subset of congenital disorders caused by mutations of the various components of the Chromatin-Marking System (CMS), including modifiers of DNA and chromatin remodelers. We performed a phenotypic study on a sample of 120 individuals harboring variants in genes codifying for the histones enzymes, using the DeepGestalt technology. Three experiments (two multiclass comparison experiments and a frontal face-crop analysis) were conducted, analyzing respectively a total of 181 pediatric images in the first comparison experiment and 180 in the second, all individuals belonging predominantly to Caucasian population. The classification results were expressed in terms of the area under the curve (AUC) of the receiver-operating-characteristic curve (ROC). Significant values of AUC and low p-values were registered for all syndromes in the three experiments, in comparison with each other, with other ID syndromes characterized by recognizable craniofacial dysmorphisms and with unaffected controls. Final findings indicated that this group of diseases is characterized by distinctive dysmorphisms, which result pathognomonic. A correct interrogation and use of adequate informatics aids, could become a valid support for clinicians.
Assuntos
Fácies , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fenótipo , Criança , Pré-Escolar , Estudos de Coortes , Diagnóstico por Imagem , Feminino , Estudos de Associação Genética/métodos , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Curva ROCRESUMO
About one child in 68 is affected by the autism spectrum disorder (ASD), one of the most common neurodevelopmental disorders linked to intellectual disability, especially in males, intellectual disability being diagnosable in about 60-70% of autistic individuals. The biological bases of ASD are not yet fully known, but they are generally considered multifactorial, although many genes and genomic loci have been proposed to be possibly associated with this condition. In this report, we describe the case of a 14-year-old female Italian proband affected by ASD, carrying a novel ~ 270 kb interstitial microduplication, localized at the distal portion of the 4q13.1 region. The rearrangement was inherited from a mild symptomatic father and included a large part of the single EPHA5 gene, a receptor tyrosine kinase involved in the neural development, already indicated to be linked to ASD by previous Genome Wide Association Studies. This imbalance represents, to the best of our knowledge, the smallest duplication identified to date that only impacts the EPHA5 gene. We hypothesize that the duplication of this gene may alter EPHA5 expression and that this may impact the autistic phenotype of the patient.
Assuntos
Transtorno do Espectro Autista/genética , Receptor EphA5/genética , Adolescente , Transtorno Autístico/genética , Hibridização Genômica Comparativa , Feminino , Duplicação Gênica/genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Deficiência Intelectual/genética , Itália , Fenótipo , Receptor EphA5/fisiologiaAssuntos
Cromossomos Humanos X/genética , Proteínas de Ligação a DNA/genética , Dedos/anormalidades , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Nariz/anormalidades , Fatores de Transcrição/genética , Adolescente , Deleção Cromossômica , Códon sem Sentido , Feminino , Humanos , Achados Incidentais , Proteínas RepressorasRESUMO
A recent syndromic condition with craniofacial dysmorphisms, comprising congenital ocular defect and neurodevelopmental delay named Helsmoortel-Van der Aa Syndrome (HVDAS) (OMIM#615873), has been described and molecularly defined, identifying pathogenic mutations in the ADNP gene (OMIM#611386) as biological cause. We report on two children, displaying intellectual disability (ID) and peculiar congenital eyes anomalies, both carrying a de novo nonsense mutation in the ADNP gene. The review of present and literature reports, suggests that the diagnosis of HVDAS should be suspected in patients with ID accompanied by behavioral features in the Autism Spectrum Disorder and distinctive craniofacial phenotype. Among dysmorphisms due to malformation of the periorbital region, ptosis appears to be particularly recurrent in HVDAS. Furthermore, the present patients could support the inclusion of the HVDAS associated with specific mutations clustering within a small ADNP genomic region among clinical conditions reminiscent of the blepharophimosis/mental retardation syndromes (BMRS).
Assuntos
Anormalidades Múltiplas/genética , Transtorno Autístico/genética , Anormalidades Craniofaciais/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Pré-Escolar , Crianças com Deficiência , Feminino , Humanos , Lactente , Masculino , Mutação , Fenótipo , SíndromeRESUMO
Mutations of SLC40A1 encoding ferroportin (Fpn), the unique cellular iron exporter, severely affect iron homeostasis causing type 4 hereditary hemochromatosis, an autosomal dominant iron overload condition with variable phenotypic manifestations. This disease can be classified as type 4A, better known as "ferroportin disease", which is due to "loss of function" mutations that lead to decreased iron export from cells, or as type 4B hemochromatosis, which is caused by "gain of function" mutations, conferring partial or complete resistance to hepcidin-mediated Fpn degradation. In this work, we discuss clinical and molecular findings on a group of patients in whom a SLC40A1 single copy missense variant was identified. Three novel variants, p.D181N, p.G204R and p.R296Q were functionally characterized. Fpn D181N and R296Q mutants can be classified as full or partial loss of function, respectively. Replacement of G204 with arginine appears to cause a more complex defect with impact both on iron export function and hepcidin sensitivity. This finding confirms the difficulty of predicting the effect of a mutation on the molecular properties of Fpn in order to provide an exhaustive explanation to the wide variability of the phenotype in type 4 hereditary hemochromatosis.