Intrafamilial Phenotypic Variability Research Articles

A Novel SPG7 Gene Pathogenic Variant in a Cypriot Family With Autosomal Recessive Spastic Ataxia.

The SPG7 gene encodes the paraplegin protein, an inner mitochondrial membrane—localized protease. It was initially linked to pure and complicated hereditary spastic paraplegia with cerebellar atrophy, and now represents a frequent cause of undiagnosed cerebellar ataxia and spastic ataxia. We hereby report the molecular characterization and the clinical features of a large Cypriot family with five affected individuals presenting with spastic ataxia in an autosomal recessive transmission mode, due to a novel SPG7 homozygous missense variant. Detailed clinical histories of the patients were obtained, followed by neurological and neurophysiological examinations. Whole exome sequencing (WES) of the proband, in silico gene panel analysis, variant filtering and family segregation analysis of the candidate variants with Sanger sequencing were performed. RNA and protein expression as well as in vitro protein localization studies and mitochondria morphology evaluation were carried out towards functional characterization of the identified variant. The patients presented with typical spastic ataxia features while some intrafamilial phenotypic variation was noted. WES analysis revealed a novel homozygous missense variant in the SPG7 gene (c.1763C > T, p. Thr588Met), characterized as pathogenic by more than 20 in silico prediction tools. Functional studies showed that the variant does not affect neither the RNA or protein expression, nor the protein localization. However, aberrant mitochondrial morphology has been observed thus indicating mitochondrial dysfunction and further demonstrating the pathogenicity of the identified variant. Our study is the first report of an SPG7 pathogenic variant in the Cypriot population and broadens the spectrum of SPG7 pathogenic variants.

Genetic Generalized Epilepsy and Intrafamilial Phenotypic Variability with Distal 7q11.23 Deletion.

Background: Distal 7q11.23 deletions are variably associated with epilepsy, intellectual disability and neurobehavioural abnormalities. The relative importance of different genes in this region in contributing to different phenotypes is not clear, though HIP1 and YWHAG are both thought to play important roles. Patients and Methods: We performed thorough phenotyping on members of a family in which multiple members carried a relatively small 0.8 Mb distal 7q11.23 deletion, affecting 17 genes. Results: Two brothers and a half-brother had all inherited the 7q11.23 deletion from their mother. The eldest two both had global developmental impairment and genetic generalized epilepsy, involving absence, myoclonic or myoclonic-atonic seizures. There was no history of seizures in the mother or her youngest son, but both also had developmental impairment. Conclusion: Distal 7q11.23 deletions affecting HIP1 and YWHAG may cause developmental impairment and genetic generalized epilepsy, with considerable intrafamilial phenotypic variability.

Short Bones, Renal Stones, and Diagnostic Moans: Hypercalcemia in a Girl Found to Have Coffin-Lowry Syndrome

Pathogenic variants in RPS6KA3 are associated with Coffin-Lowry syndrome (CLS), an X-linked semidominant disorder characterized by intellectual disability, stimulus-induced drop attacks, distinctive facial features, progressive kyphoscoliosis, and digit anomalies in hemizygous males. Heterozygous females may also have features of CLS; however, there can be considerable phenotypic variation, often attributed to ratios of X-inactivation in various tissue types. Although skeletal anomalies and short stature are hallmarks of CLS, hypercalcemia has not been reported. Here we describe a 30-month-old girl with gross motor delays, short stature, dysmorphic features, bilateral duplicated renal collecting systems, and no family history of hypercalcemia who required multiple admissions for idiopathic hypercalcemia necessitating bisphosphonate infusions at 12.5 and 15 months of age. A maternally inherited likely-pathogenic variant in RPS6KA3 was identified by trio exome sequencing, consistent with the diagnosis of CLS in the proband and her mother. Maternal history was notable only for decreased height compared to first-degree relatives, bilateral genu valgum, and a bicornuate uterus; she was later found to also have a partially duplicated left renal collecting system. Subsequent X-inactivation studies in blood aligned with the phenotypic variation between mother and daughter. Although hypercalcemia is not a reported feature in CLS, there is evidence of interrupted osteoblast differentiation, providing a potential mechanism for hypercalcemia in this genetic condition. The hypercalcemia in this case may represent a severe presentation of an unrecognized clinical feature in CLS that resolves with age. This case further highlights the intrafamilial phenotypic variation of CLS among females, suggesting X-inactivation as the underlying mechanism, and demonstrates the value of exome sequencing in patients for whom a genetic disorder is highly suspected but not identified despite thorough evaluation.

Identification of a PROM1 mutation in a Spanish family with inherited retinal dystrophies

Background: We report a Spanish family, comprising an affected mother and daughter, respectively diagnosed with retinitis pigmentosa and Stargardt-like macular dystrophy, in whom we identified a PROM1 mutation. Methods: A custom gene panel consisting of 119 inherited retinal dystrophies (IRD)-genes was applied in the two affected individuals of this family and sequenced using the Illumina´s NextSeq500 platform. Results: The analysis of the resulting data allowed us to identify the pathogenic PROM1 mutation c.1117C>T (p.Arg373Cys) as the primary cause of the disease in both patients. No additional variants contributing to the extent of retinal dysfunction were detected. Conclusion: The variable expressivity of the detected PROM1 mutation is the most likely responsible for the intrafamilial phenotypic variability observed in this family. Screening of this mutation should be considered in patients with compatible clinical manifestations, especially when accompanied by an autosomal dominant family history.

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families

PurposeBiallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants.MethodsSynthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized.ResultsAmong the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity.ConclusionWe expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan.

Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40’s; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.

Gene Mutations of the Three Ectodysplasin Pathway Key Players (EDA, EDAR, and EDARADD) Account for More than 60% of Egyptian Ectodermal Dysplasia: A Report of Seven Novel Mutations.

Ectodermal dysplasia (ED) is a diverse group of genetic disorders caused by congenital defects of two or more ectodermal-derived body structures, namely, hair, teeth, nails, and some glands, e.g., sweat glands. Molecular pathogenesis of ED involves mutations of genes encoding key proteins of major developmental pathways, including ectodysplasin (EDA) and wingless-type (WNT) pathways. The most common ED phenotype is hypohidrotic/anhidrotic ectodermal dysplasia (HED) featuring hypotrichosis, hypohidrosis/anhidrosis, and hypodontia. Molecular diagnosis is fundamental for disease management and emerging treatments. We used targeted next generation sequencing to study EDA, EDAR, EDARADD, and WNT10A genes in 45 Egyptian ED patients with or without hypohidrosis. We present genotype and phenotype data of 28 molecularly-characterized patients demonstrating genetic heterogeneity, variable expressivity, and intrafamilial phenotypic variability. Thirteen mutations were reported, including four novel EDA mutations, two novel EDARADD, and one novel EDAR mutations. Identified mutations congregated in exons encoding key functional domains. EDA is the most common gene contributing to 85% of the identified Egyptian ED genetic spectrum, followed by EDARADD (10%) and EDAR (5%). Our cohort represents the first and largest cohort from North Africa where more than 60% of ED patients were identified emphasizing the need for exome sequencing to explore unidentified cases.

Intrafamilial Variability of Ocular Manifestations of von Hippel-Lindau Disease

In this retrospective cohort study, we describe intrafamilial phenotypic variability of retinal hemangioblastoma (RH) in families with von Hippel-Lindau (VHL) disease. Patients with molecularly-confirmed VHL evaluated at our institution were identified and records reviewed. For individuals with sufficient follow up and imaging (n=27), number and location of RHs at the initial and most recent follow up visits were recorded along with treatment method and systemic manifestations. A strategy for zonal classification of RH location was used. Intrafamilial phenotypic variation was identified in 3 families. Intrafamilial phenotypic variability of RH exists between family members with VHL with the same genetic mutation.

Genetic and epigenetic disease modifiers in an Italian C9orf72 family expressing ALS, FTD or PD clinical phenotypes

Objective: The presence of the hexanucleotide repeat expansion (HRE) in C9orf72 gene is associated to the ALS/FTD spectrum, but also to parkinsonisms. We here describe an Italian family with the father diagnosed with Parkinson disease (PD) at the age of 67 and the two daughters developing FTD and ALS at 45 years of age. We searched for C9orf72 HRE with possible genetic and epigenetic modifiers to account for the intrafamilial phenotypic variability. Methods: C9orf72 mutational analysis was performed by fragment length analysis, Repeat-primed PCR and Southern blot. Targeted next generation sequencing was used to analyze 48 genes associated to neurodegenerative diseases. Promoter methylation was analyzed by bisulfite sequencing. Results: Genetic analysis identified C9orf72 HRE in all the affected members with a similar repeat expansion size. Both the father and the FTD daughter also carried the heterozygous p.Ile946Phe variant in ATP13A2 gene, associated to PD. In addition, the father also showed a heterozygous EIF4G1 variant (p.Ala13Pro), that might increase his susceptibility to develop PD. The DNA methylation analysis showed that all the 26 CpG sites within C9orf72 promoter were unmethylated in all family members. Conclusions: Neither C9orf72 HRE size nor promoter methylation act as disease modifiers within this family, at least in blood, not excluding HRE mosaicism and a different methylation pattern in the brain. However, the presence of rare genetic variants in PD genes suggests that they may influence the clinical manifestation in the father. Other genetic and/or epigenetic modifiers must be responsible for disease variability in this C9orf72 family case.

Clinical and molecular characteristics of 168 probands and 65 relatives with a clinical presentation of classical Ehlers-Danlos syndrome.

Classical Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder mainly caused by pathogenic variants in COL5A1 or COL5A2, encoding type V collagen. Its diagnosis, based on clinical criteria and molecular confirmation, can be challenging. We report the molecular and clinical characteristics of 168 probands (72 clinically evaluated at our center) and 65 relatives with a clinical presentation of cEDS. Type V collagen defects were found in 145 probands, 121 (83.5%) were located in COL5A1 and 24 (16.5%) in COL5A2. Although 85.6% of molecularly confirmed patients presented the two major clinical criteria (generalized joint hypermobility, hyperextensible skin with atrophic scarring), significant inter- and intrafamilial phenotypic variability was noted. COL5A2 variants often caused a more severe phenotype. Vascular complications were rare in individuals with type V collagen defects (1.4%). Among the 72 probands clinically evaluated in our center, the mutation detection rate was 82.0%. The majority (68.1%) harbored COL5A1/COL5A2 defects. Yet, 13.9% harbored a defect in another gene (COL1A1, PLOD1, TNXB, AEBP1) highlighting important clinical overlap and the need for molecular confirmation of the diagnosis as this has implications regarding follow-up and genetic counseling. Eighteen percent of the 72 probands remained molecularly unexplained and a COL5A1 variant of unknown significance was identified in 6.9%.

Recognizing Atypical Dopa-Responsive Dystonia and Its Mimics.

Dopa-responsive dystonia (DRD) encompasses a group of phenotypically and genetically heterogeneous neurochemical disorders. Classic GTP cyclohydrolase 1 (GCH-1)-associated DRD consists of early-onset lower limb asymmetrical dystonia, with sleep benefit, diurnal variation, and excellent and sustained response to low l-dopa doses. Unlike the classic phenotype, GCH-1-associated DRD may include features inconsistent with the original phenotype. We describe a GCH-1-associated late-onset DRD case with a family history of parkinsonism and cervical dystonia whose response to levodopa was poor and complicated with dyskinesia, blepharospasm, and severe nonmotor symptoms. We use this case as a springboard to review the spectrum of atypical DRD, DRD-plus, and DRD mimics. GCH-1-related dystonia may exhibit wide intrafamilial phenotypic variability, no diurnal fluctuation, poor response to l-dopa, and such complications as dyskinesia, epilepsy, sleep disorders, autonomic dysfunction, oculogyric crisis, myoclonus, or tics. More recently, rare GCH-1 variants have been found to be associated with Parkinson disease. Clinicians should be aware of atypical DRD, DRD-plus, and DRD mimics.

An intrafamilial phenotypic variability in Ellis-Van Creveld syndrome due to a novel 27 bps deletion mutation.

Ellis-van Creveld (EvC) syndrome is an autosomal recessive disease, characterized by ectodermal, skeletal, and cardiac anomalies. We report intrafamilial phenotypic variability in three new EvC syndrome cases. Affected males in this study showed only ectodermal abnormalities, whereas an affected female showed the classical presentation of EvC Syndrome, including bilateral postaxial polydactyly of hands and feet, and congenital heart defects. Whole exome sequencing was performed to identify the causative variant, followed by validation and segregation analysis using Sanger sequencing. A homozygous deletion variant (c.731_757del) was identified in exon 6 of the EVC gene (NM_153717.2). The identified variant is considered to be the most likely candidate variant for the EvC syndrome in the family based on previous reports validating the role of EVC variants in the EvC syndrome. The disease correctly segregated in the family members, as all affected members were homozygous, and obligate carriers were heterozygous. Our family is remarkable in highlighting the variable expressivity of the EvC phenotype within the same family, due to a homozygous deletion mutation in the EVC gene. The variable expressivity might be due to the hypomorphic nature of mutation, or the presence of additional variants in modifier genes or in the regulatory regions of the EVC/EVC2 genes.

Identification of modifier genes underlying intra-familial phenotypic variability in zebrafish OI models using whole exome sequencing (WES) and linkage analysis

Identification of modifier genes underlying intra-familial phenotypic variability in zebrafish OI models using whole exome sequencing (WES) and linkage analysis

Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy.

High-throughput sequencing (HTS) improved the molecular diagnosis in individuals with intellectual deficiency (ID) and helped to broaden the phenotype of previously known disease-causing genes. We report herein four unrelated patients with isolated ID, carriers of a likely pathogenic variant in KCNQ2, a gene usually implicated in benign familial neonatal seizures (BFNS) or early onset epileptic encephalopathy (EOEE). Patients were diagnosed by targeted HTS or exome sequencing. Pathogenicity of the variants was assessed by multiple in silico tools. Patients' ID ranged from mild to severe with predominance of speech disturbance and autistic features. Three of the four variants disrupted the same amino acid. Compiling all the pathogenic variants previously reported, we observed a strong overlap between variants causing EOEE, isolated ID, and BFNS and an important intra-familial phenotypic variability, although missense variants in the voltage-sensing domain and the pore are significantly associated to EOEE (p < 0.01, Fisher test). Thus, pathogenic variants in KCNQ2 can be associated with isolated ID. We did not highlight strong related genotype-phenotype correlations in KCNQ2-related disorders. A second genetic hit, a burden of rare variants, or other extrinsic factors may explain such a phenotypic variability. However, it is of interest to study encephalopathy genes in non-epileptic ID patients.

Germ cell mosaicism for AUTS2 exon 6 deletion

Haploinsufficiency of AUTS2 has been associated with neurodevelopmental disorders and dysmorphic features (MIM # 615834). More than 50 patients have been described, mostly carrying de novo deletions of one or more exons, including eight patients with exon 6 deletions. We report on two siblings, a girl and a boy aged 11 and 13 years, in whom the same pathogenic 85 kb deletion on 7q11.22 encompassing exon 6 of AUTS2 by SNP array analysis was identified. Both children had typical symptoms of AUTS2 syndrome such as intellectual impairment and behavioral problems, but with markedly different expression. SNP array analysis excluded the deletion in blood samples of both parents and a healthy brother. Conventional karyotyping of both parents and additional FISH analyses, marking the flanking regions of the deletion, did not show any structural rearrangements involving 7q11.22. A germ cell mosaicism was suggested as the most probable explanation for occurrence of the same deletion in these two siblings. To our knowledge this is the first report of germ cell mosaicism for AUTS2 syndrome. It additionally provides further evidence of intrafamilial phenotypic variability in AUTS2 syndrome and adds clinical information to the phenotypic spectrum of patients with AUTS2 exon 6 deletions.

Hypoparathyroidism as the single major component for decades of autoimmune polyglandular syndrome type 1.

SummaryAutoimmune polyglandular syndrome type 1 (APS-1) is a very rare autoimmune entity, accounting for about 400 cases reported worldwide. It is characterized by the presence of at least two of three cardinal components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison’s disease. It typically manifests in childhood with CMC and years later with hypoparathyroidism. A 50-year-old man was referred to the Endocrinology outpatient clinic due to irregular follow-up of primary hypoparathyroidism diagnosed at age 7. Previous analysis reported frequent fluctuations of calcium and phosphate levels and persistent hypercalciuria. He presented several comorbidities, including bilateral cataracts, other ocular disorders, transient alopecia and chronic gastritis. Due to weight loss, fatigue, gastrointestinal complaints and the findings at objective examination, Addison’s disease and CMC were investigated and confirmed. Antifungal therapy and hormonal replacement were started with evident clinical improvement. Regarding hypoparathyroidism, calcium-phosphate product decreased and other extraskeletal calcifications were diagnosed, such as nephrolithiasis and in basal ganglia. Further evaluation by genetic analysis revealed homozygosity for a frameshift mutation considered to be a pathogenic variant. It was reported only in two Asian siblings in compound heterozygosity. This case highlights the broad phenotypic spectrum of APS-1 and the significative intra-familial phenotype variability. A complete clinical history taking and high index of suspicion allowed the diagnosis of this rare entity. This case clarifies the need for regular long-term follow-up. In the specific case of hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex.Learning points:Autoimmune polyglandular syndrome type 1 (APS-1) is a deeply heterogeneous genetic entity with a broad spectrum of clinical manifestations and a significant intra-family phenotypic variability.Early diagnosis of APS-1 is challenging but clinically relevant, as endocrine and non-endocrine manifestations may occur during its natural history.APS-1 should be considered in cases of acquired hypoparathyroidism, and even more so with manifestations with early onset, family history and consanguinity.APS-1 diagnosis needs a high index of suspicion. Key information such as all the comorbidities and family aspects would never be valued in the absence of a complete clinical history taking.Especially in hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex and is not a matter of simply approaching individually each condition.Regular long-term monitoring of APS-1 is essential. Intercalary contact by phone calls benefits the control of the disease and the management of complications.

Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability.

ObjectiveOur aim was to study a Hungarian family with autosomal dominantly inherited neurodegeneration with brain iron accumulation (NBIA) with markedly different intrafamilial expressivity.MethodsTargeted sequencing and multiplex ligation-dependent probe amplification (MLPA) of known NBIA-associated genes were performed in many affected and unaffected members of the family. In addition, a trio whole-genome sequencing was performed to find a potential explanation of phenotypic variability. Neuropathologic analysis was performed in a single affected family member.ResultsThe clinical phenotype was characterized by 3 different syndromes—1 with rapidly progressive dystonia-parkinsonism with cognitive deterioration, 1 with mild parkinsonism associated with dementia, and 1 with predominantly psychiatric symptoms along with movement disorder. A heterozygous stop-gain variation in the C19Orf12 gene segregated with the phenotype. Targeted sequencing of all known NBIA genes, and MLPA of PLA2G6 and PANK2 genes, as well as whole-genome sequencing in a trio from the family, revealed a unique constellation of oligogenic burden in 3 NBIA-associated genes (C19Orf12 p.Trp112Ter, CP p.Val105PhefsTer5, and PLA2G6 dup(ex14)). Neuropathologic analysis of a single case (39-year-old man) showed a complex pattern of alpha-synucleinopathy and tauopathy, both involving subcortical and cortical areas and the hippocampus.ConclusionsOur study expands the number of cases reported with autosomal dominant mitochondrial membrane protein-associated neurodegeneration and emphasizes the complexity of the genetic architecture, which might contribute to intrafamilial phenotypic variability.

Inter- and Intrafamilial Phenotypic Variability in Individuals with Collagen-Related Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a rare genetic disorder also known as a “brittle bone disease.” Around 90% of patients with OI harbor loss‐of‐function or dominant negative pathogenic variants in the COL1A1 and COL1A2 genes, which code for collagen type I α1 and α2 chains. Collagen‐related forms of the disorder are classified as Sillence OI types I–IV. OI phenotype expression ranges from mild to lethal. The current study aims to evaluate associations between interfamilial and intrafamilial phenotypic variability and genotype characteristics of patients with collagen‐related OI. The study was based on a systematic review of collagen‐related OI cases from the University of Tartu OI database (n = 137 individuals from 81 families) and the Dalgleish database (n = 479 individuals). Interfamilial variability analysis has shown that 17.74% of all studied OI‐related variants were associated with the same phenotype. The remaining 82.26% of pathogenic variants were associated with variable phenotypes. Additionally, higher interfamilial variability correlated with the COL1A1 gene (P value = 0.001) and dominant‐negative variants (P value = 0.0007). Within intrafamilial variability, 32.81% families had increasing or decreasing OI phenotype severity across generations. Higher intrafamilial variability of phenotypes correlated with the collagen I dominant negative variants (P value = 0.0246). The current study shows that, in line with other phenotype modification factors, OI interfamilial and intrafamilial diversity potential is associated with the genotype characteristics of the OI‐causing pathogenic variants. The results of the current study may advance knowledge of OI phenotype modification as well as assist family planning and the evaluation of disease progression in subsequent generations.

Juvenile Paget’s disease: Report of a family with a novel missense mutation and unique radiological manifestations in a heterozygote

Abstract Juvenile Paget’s disease (JPD) is a rare, generalized skeletal disorder characterized by markedly increased bone turnover secondary to enhanced osteoclastic activity. The patients with JPD develop progressive, widespread skeletal involvement and non-skeletal manifestations. Objectives To identify the characteristic molecular, biochemical, radiological, and audiological findings in three siblings with JPD associated with intrafamilial phenotypic variability. Patients and Methods A Saudi family with 3 affected siblings was recruited. Biochemical measurement of serum alkaline phosphatase and markers of bone turnover were performed. Genetic testing and sequencing of a panel of 22 known genes for skeletal dysplasia with increase bone density were performed by next generation sequencing (NGS). Radiological and audiological assessment were also performed. Results Patients showed marked elevation of serum alkaline phosphatase and markers of bone turnover. A novel homozygous mutation c.433T&amp;gt;G (p.Cys145Gly) in exon 3 of TNFRSF11B gene was identified in the 3 affected siblings. Both parents were heterozygous for the mutation. The heterozygote father had thickening of calvarium, a radiological manifestation of JPD. The eldest child (index case) had a unique striking distortion of the skull bones as evidenced by 3-D computed tomography of skull. He had also bilateral inner ear structural deformity and severe sensorineural hearing loss. Conclusions: JPD is a rare disorder that can be highly overlooked due to phenotypic overlap with other disorders of skeletal dysplasia. Mutations affecting cysteine residues result in the most severe JPD phenotypes. NGS is useful for early diagnosis of JPD, a prerequisite for successful treatment strategy.

CLCN1 Molecular Characterization in 19 South-Italian Patients With Dominant and Recessive Type of Myotonia Congenita.

Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia). It is caused by mutations in the CLCN1 gene, encoding the voltage-gated chloride channel of skeletal muscle, ClC-1. According to the pattern of inheritance, two distinct clinical forms have been described, Thomsen disease, inherited as an autosomal dominant trait and Becker disease inherited as an autosomal recessive trait. We report genetic and clinical data concerning 19 patients−13 familial and six isolated cases—all but one originating from the Campania Region, in southern Italy. Twelve patients (63.2%) present Becker type myotonia and 7 (36.8%) Thomsen type. Sex ratio M:F in Becker type is 6:6, while in Thomsen myotonia 4:3. The age of onset of the disease ranged from 2 to 15 years in Becker patients, and from 4 to 20 years in Thomsen. Overall 18 mutations were identified, 10 located in the coding part of the gene (exons 1, 3, 4, 5, 7, 8, 13, 15, 21, 22), and four in the intron part (introns 1, 2, 10, 18). All the exon mutations but two were missense mutations. Some of them, such as c.2551 G > A, c.817G > A and c.86A > C recurred more frequently. About 70% of mutations was inherited with an autosomal recessive pattern, two (c.86A and c.817G>A) with both mechanisms. Three novel mutations were identified, never described in the literature: p.Gly276Ser, p.Phe486Ser, and p.Gln812*, associated with Becker phenotype. Furthermore, we identified three CLCN1 mutations—c.86A>C + c.2551G > A, c.313C > T + c.501C > G and 899G > A + c.2284+5C > T, two of them inherited in cis on the same allele, in three unrelated families. The concomitant occurrence of both clinical pictures—Thomsen and Becker—was observed in one family. Intra-familial phenotypic variability was observed in two families, one with Becker phenotype, and one with Thomsen disease. In the latter an incomplete penetrance was hypothesized.