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We report on a pediatric patient with skin fragility suggestive for classical Ehlers–Danlos syndrome (cEDS) but without marked skin hyperextensibility, who came to our attention with unconvincing results of an external next generation sequencing (NGS) panel that included all cEDS‐associated genes. Based on a phenotype‐first approach, mainly due to the presence of typical atrophic scars, we made a clinical diagnosis of cEDS. We explored for an intragenic rearrangement in COL5A1 by MLPA, ruled out the classical‐like EDS type 2 by sequencing of AEBP1, and finally resequenced COL5A1 with the Sanger method that documented a novel intragenic duplication. Our findings show that in some cEDS patients the skin might not be markedly hyperextensible and that the cutaneous hallmark of the disorder is characterized by the presence of multiple, widened atrophic scars. This report is also a good example on how the new sequencing technologies are not foolproof and suggest that clinicians should look beyond negative NGS testing when there is a sufficiently clear phenotypic indication.

Background New drugs that target the basic defect in cystic fibrosis (CF) patients may now be used in a large number of patients carrying responsive mutations. Nevertheless, further research is needed to extend the benefit of these treatments to patients with rare mutations that are still uncharacterized in vitro and that are not included in clinical trials. For this purpose, ex vivo models are necessary to preliminary assessing the effect of CFTR modulators in these cases. Method We report the clinical effectiveness of lumacaftor/ivacaftor therapy prescribed to a CF child with a rare genetic profile (p.Phe508del/p.Gly970Asp) after testing the drug on nasal epithelial cells. We observed a significant drop of the sweat chloride value, as of the lung clearance index. A longer follow‐up period is needed to define the effects of therapy on pancreatic status, although an increase of the fecal elastase values was found. Conclusion Drug response obtained on nasal epithelial cells correlates with changes in vivo therapeutic endpoints and can be a predictor of clinical efficacy of novel drugs especially in pediatric patients. Drug response obtained on nasal epithelial cells correlates with changes in vivo therapeutic endpoints and can be a predictor of clinical efficacy of novel drugs especially in pediatric patients.

Background Alterations of vacuolar protein sorting‐associated protein 13 (VPS13) family members including VPS13A, VPS13B, and VPS13C lead to chorea acanthocytosis, Cohen syndrome, and parkinsonism, respectively. Recently, VPS13D mutations were identified as a cause of VPS13D‐related movement disorders, which show several phenotypes including chorea, dystonia, spastic ataxia, and spastic paraplegia. Methods We applied whole‐exome analysis for a patient with a complicated form of hereditary spastic paraplegia (HSP) and her unaffected parents. Then, we screened the candidate genes in 664 Japanese families with HSP in Japan. Results We first found a compound heterozygote VPS13D mutation and a heterozygote ABHD4 variation in a sporadic patient with spastic paraplegia. Then, we found three patients with VPS13D mutations in two Japanese HSP families. The three patients with homozygous mutations (p.Thr1118Met/p.Thr1118Met and p.Thr2945Ala/p.Thr2945Ala) in the VPS13D showed an adult onset pure form of HSP. Meanwhile, the patient with a compound heterozygous mutation (p.Ser405Arg/p.Arg3141Ter) in the VPS13D showed a childhood onset complicated form of HSP associated with cerebellar ataxia, cervical dystonia, cataracts, and chorioretinal dystrophy. Conclusion In the present study, we found four patients in three Japanese families with novel VPS13D mutations, which may broaden the clinical and genetic findings for VPS13D‐related disorders. We identified four Japanese patients with VPS13D‐related disorders presenting as a pure or a complicated form of HSP.

Background Biallelic pathogenic variants in SLC5A6 resulting in sodium‐dependent multivitamin transporter (SMVT) defect have recently been described as a vitamin‐responsive inborn error of metabolism mimicking biotinidase deficiency. To our knowledge, only 16 patients have been reported so far with various clinical phenotypes such as neuropathy and other neurologic impairments, gastro‐intestinal dysfunction and failure to thrive, osteopenia, immunodeficiency, metabolic acidosis, hypoglycemia, and recently severe cardiac symptoms. Methods We describe a case report of a 5‐month‐old girl presenting two recurrent episodes of metabolic decompensation and massive cardiac failure in the course of an infectious disease. We compare clinical, biological, and genetic findings of this patient to previous literature collected from Pubmed database (keywords: Sodium‐dependent multivitamin transporter (SMVT), SMVT defect/disorder/deficiency, SLC5A6 gene/mutation). Results We highlight the life‐threatening presentation of this disease, the stagnation of psychomotor development, the severe and persistent hypogammaglobulinemia, and additionally, the successful clinical response on early vitamin supplementation (biotin 15 mg a day and pantothenic acid 100 mg a day). Metabolic assessment showed a persistent increase of urinary 3‐hydroxyisovaleric acid (3‐HIA) as previously reported in this disease in literature. Conclusion SMVT deficiency is a vitamin‐responsive inborn error of metabolism that can lead to a wide range of symptoms. Increased and isolated excretion of urinary 3‐hydroxyisovaleric acid may suggest, in the absence of markedly reduced biotinidase activity, a SMVT deficiency. Prompt supplementation with high doses of biotin and pantothenic acid should be initiated while awaiting results of SLC5A6 sequencing as this condition may be life‐threatening. We highlight the life‐threatening presentation of SMVT deficiency. Increased and isolated excretion of urinary 3‐hydroxyisovaleric acid may suggest, in the absence of markedly reduced biotinidase activity, a SMVT deficiency. Prompt supplementation with high doses of biotin and pantothenic acid should be initiated while awaiting results of SLC5A6 sequencing as this condition may be life‐threatening and a high dose of these water‐soluble vitamins seems harmless.

Background Phosphoserine aminotransferase deficiency (PSATD) is an autosomal recessive disorder associated with hypertonia, psychomotor retardation, and acquired microcephaly. Patients with PSATD have low concentrations of serine in plasma and cerebrospinal fluid. Methods We reported a 2‐year‐old female child with developmental delay, dyskinesia, and microcephaly. LC–MS/MS was used to detect amino acid concentration in the blood and whole‐exome sequencing (WES) was used to identify the variants. PolyPhen‐2 web server and PyMol were used to predict the pathogenicity and changes in the 3D model molecular structure of protein caused by variants. Results WES demonstrated compound heterozygous variants in PSAT1, which is associated with PSATD, with a paternal likely pathogenic variant (c.235G>A, Gly79Arg) and a maternal likely pathogenic variant (c.43G>C, Ala15Pro). Reduced serine concentration in LC–MS/MS further confirmed the diagnosis of PSATD in this patient. Conclusions Our findings demonstrate the importance of WES combined with LC–MS/MS reanalysis in the diagnosis of genetic diseases and expand the PSAT1 variant spectrum in PSATD. Moreover, we summarize all the cases caused by PSAT1 variants in the literature. This case provides a vital reference for the diagnosis of future cases. We reported a 2‐year‐old female child with developmental delay, dyskinesia, and microcephaly. The patient was eventually diagnosed as PSATD by WES combined with LC–MS/MS reanalysis. This case provides a vital reference for the diagnosis of future genetic disease cases.

Background Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next‐generation sequencing (NGS) for classification of unselected sarcomas remains controversial. Methods and Results We report a case of a metastatic sarcoma in a 34‐year‐old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as IMT after NGS revealed a TFG‐ROS1 rearrangement. Histologically, the neoplasm had spindle cell morphology with a lobulated to focally infiltrative growth pattern with scant inflammatory cell infiltrate. Immunohistochemistry demonstrated focal desmin and variable smooth muscle actin staining but was negative for SOX10, S100, and CD34. Fluorescence in situ hybridization was negative for USP6 or ALK gene rearrangements. NGS revealed a TFG‐ROS1 rearrangement and the patient was treated with crizotinib with clinical benefit. Conclusions We discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK‐negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment. We report a case of a metastatic sarcoma in a 34‐year‐old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as inflammatory myofibroblastic tumor after next‐generation sequencing (NGS) revealed a TFG‐ROS1 rearrangement. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.

Background The protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause rhizomelic limb shortening with dysmorphic features. Case Report A fetus was found to be rhizomelic limb shortening at 16 weeks of gestation and amniocentesis was performed at 19 weeks of gestation. Genomic DNA extracted from the amniotic fluid was subjected to chromosomal microarray analysis (CMA), and Trio‐total whole‐exome sequencing (Trio‐WES). Sanger sequencing was used to verify the candidate pathogenic variants. CMA was normal, while Trio‐WES identified two compound heterozygous variants in the PKDCC gene, namely c.417_c.423delCGGCGCG insTCATGGGCTCAGTACAC(p.G140fs*35) and c.345G>A (p.W115*,379). Then the fetus was aborted and the development of its bone cells were compared with that of a normal fetus of similar gestational age by histopathological examination. Clinical findings of the fetus were shortening humerus and femur, synophrys, much hair on the side face, simian line on the right palm, etc. Histopathological examination showed that the affected fetus had increased proliferative chondrocytes, widened proliferative bands, and delayed bone mineralization. Conclusions We reported a prenatal case of rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene, which emphasized the important role of Trio‐WES for diagnosis of skeletal dysplasia in fetuses. Novel compound heterozygous variants in the protein kinase domain containing cytoplasmic gene can cause fetal rhizomelic shortening of limbs.

Introduction Leber congenital amaurosis (LCA) type 2, due to disease‐causing variants in RPE65, is characterized by severe visual loss in early infancy. Current treatments include voretigene neparvovec‐rzyl (VN) for RPE65‐associated LCA. Herein, we present the long‐term follow‐up of a patient treated with VN using quantitative autofluorescence (488 nm excitation). Case Report A 9‐year‐old girl with a diagnosis of LCA with biallelic variants in RPE65 presented for evaluation. The patient underwent VN treatment at the age of 11. The patient returned to clinic at age of 19 at which time imaging revealed evidence of chorioretinal atrophy. Quantitative autofluorescence performed prior to gene therapy and at 6‐ and 8‐year follow‐up revealed a central area of fundus autofluorescence. Discussion This case report demonstrates acquisition of fundus autofluorescence at 6‐ and 8‐year follow‐up despite the development of chorioretinal atrophy. We present eight‐year follow‐up of a patient treated with voretigiene neparvovec‐rzyl (VN) who presented with chorioretinal atrophy at eight‐year follow‐up. Quantitative autofluorescence at six‐ and eight‐year follow‐up demonstrates presence of autofluorescence suggestive of the continued efficacy of VN despite the presence of chorioretinal atrophy.

Background Hyperparathyroidism jaw‐tumor syndrome (HPT‐JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT‐JT have a 15–20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients. Case Report Here are report two atypical cases of HPT‐JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first‐line panel by Next‐Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT‐JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait. Conclusion In view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis. We report two atypical cases of hyperparathyroidism jaw‐tumor syndrome with variable expressivity within the same family. The index case, a young woman with isolated primary hyperparathyroidism, underwent panel sequencing of genes involved in familial primary hyperparathyroidism. A variation of the CDC73 gene was found. The segregation study identified the variation in his mother who had a history of hyperparathyroidism associated with adenomyosis.

Background The ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease characterized by cerebral anomalies. These patients have congenital microcephaly, progressive encephalopathy, severe intellectual disability, and intractable seizures. Method Clinical characteristics of the patient were collected. Exome sequencing was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. The structure of the protein was checked using the DynaMut2 web server. Results The proband is an 11‐year‐old Iranian‐Azeri girl with primary microcephaly and severe intellectual disability in a family with a consanguineous marriage. Symptoms emerged around the 10–20th days of life, when refractory epileptic gaze and unilateral tonic–clonic seizures initiated without any provoking factor such as fever. A brain MRI revealed no abnormalities except for brain atrophy. The karyotype was normal. Using exome sequencing, we identified a novel homozygous variant of thymine to adenine (NM_001673.5:c.538T>A) in the ASNS gene. Both parents had a heterozygous variant in this location. Subsequently, Sanger sequencing confirmed this variant. We also reviewed the clinical manifestations and MRI findings of the previously reported patients. Conclusion In the present study, a novel homozygous variant was recognized in the ASNS gene in an Iranian‐Azeri girl manifesting typical ASNSD symptoms, particularly intellectual disability and microcephaly. This study expands the mutation spectrum of ASNSD and reviews previously reported patients. A novel alteration of thymine to adenine was identified, using exome sequencing analysis in the ASNS gene. Isoleucine amino acid replacing phenylalanine destabilizes the protein structure. We also reviewed the clinical manifestations and MRI findings of 75 previously reported patients suffering from asparagine synthetase deficiency.