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Blind-side hypermelanosis has emerged as a major concern in flatfish aquaculture worldwide, including tongue sole (Cynoglossus semilaevis) in China. The causative gene and the molecular basis are still unclear. In this study, comparative transcriptome analyses were performed using different skin tissues of tongue sole: ocular-side normal (pigmented) skin, blind-side normal (non-pigmented) skin and blind-side hypermelanotic (pigmented) skin. Finally, 60 key hypermelanosis-related genes were mined, providing potential candidate gene resources involved in blind-side hypermelanosis. These genes were selected based on the log2(FoldChange) and false discovery rate (FDR) values (with corresponding P-Values

The article discusses the problem of differential diagnosis and treatment of patients with Angelman syndrome (AS). It provides the most common syndromes with similar to AS phenotypes, the main differences between AS-like syndromes, indicating the causative gene. Much attention is given to the basic directions of treating patients with Angelman syndrome: organization of regime, syndromic treatment, providing psychological, speech therapy, orthopedic services, occupational therapy, activities aimed at social adaptation. This article contains the latest information about modern progressive directions of AS medical management. To optimize the diagnostic and therapeutic process, data about international Angelman syndrome foundations are shown., Статья посвящена проблеме дифференциальной диагностики и лечения больных с синдромом Ангельмана (AS). Представлены наиболее часто встречающиеся синдромы, имеющие сходные с AS фенотипические проявления, приведены основные дифференциальные отличия AS-подобных синдромов с указанием причинно-значимого гена. Большое внимание уделено основным направлениям лечения больных с синдромом Ангельмана: организации режима, посиндромной терапии, оказанию психологической, логопедической, ортопедической помощи, трудотерапии, мероприятиям, направленным на социальную адаптацию. Статья содержит новейшую информацию о современных прогрессивных направлениях медикаментозного управления AS. Для оптимизации диагностического и терапевтического процессов приведены данные о международных фондах синдрома Ангельмана., Стаття присвячена проблемі диференційної діагностики та лікування хворих iз синдромом Ангельмана (AS). Представлені синдроми, що зустрiчаються найчастіше, які мають схожі з AS фенотипічні прояви, наведені основні диференційні відмінності AS-подібних синдромів із зазначенням причинно-значущого гена. Велику увагу приділено основним напрямкам лікування хворих iз синдромом Ангельмана: організації режиму, посиндромнiй терапії, наданню психологічної, логопедичної, ортопедичної допомоги, трудотерапії, заходам, спрямованим на соціальну адаптацію. Стаття містить новітню інформацію про сучасні прогресивні напрямки медикаментозного управління AS. Для оптимізації діагностичного та терапевтичного процесів наведені дані про міжнародні фонди синдрому Ангельмана.

The nemaline myopathies constitute a large proportion of the congenital or structural myopathies. Common to all patients is muscle weakness and the presence in the muscle biopsy of nemaline rods. The causative genes are at least twelve, encoding structural or regulatory proteins of the thin filament, and the clinical picture as well as the histological appearance on muscle biopsy vary widely. Here, we suggest a renewed clinical classification to replace the original one, summarise what is known about the pathogenesis from mutations in each causative gene to the forms of nemaline myopathy described to date, and provide perspectives on pathogenetic mechanisms possibly open to therapeutic modalities.

Lateral meningocele syndrome is characterized by multiple lateral meningoceles with a distinctive craniofacial appearance, hyperextensibility of the skin, and hypermobility of the joints. The syndrome is caused by heterozygous truncating variants in the last exon, exon 33, of the NOTCH3 gene. Here, we present a 2-year-old girl for whom an early genomic analysis allowed us to recognize the presence of lateral meningoceles and to begin early monitoring of her condition for possible neurological complications. She had a characteristic facial appearance, hyperextensibility of the skin and mobility of the joints, and developmental delays. Given that lateral meningocele syndrome is a rare syndrome, the existence of lateral meningoceles is suspected only when the causative gene is detected by genetic testing. MRI scans are unlikely to be performed in infancy in the absence of neurological symptoms suggestive of meningoceles. No formal guidelines have been established for the neurosurgical indications for lateral meningocele syndrome. Given the features of hyperextensibility of the skin and hypermobility of the joints, lateral meningocele syndrome can be categorized as a connective tissue disease and may be progressive, as with the dural ectasia in Marfan syndrome and Loeys-Dietz syndrome. Watchful monitoring of dural ectasia may be warranted in patients with lateral meningocele syndrome.

Parkinson’s disease (PD) is caused by a combination of genetic and environmental factors. Notably, genetic risk factors vary according to ethnicity and geographical regions, and few studies have analyzed the frequency of PD causative genes in Japanese patients. Therefore, we performed genetic analyses of Japanese patients with PD. We recruited 221 participants, including 26 patients with familial PD. Genetic risk factors were evaluated by target sequencing and gene dosage analysis. We detected the genetic risk factors in 58 cases (26.2%) and classified patients into three groups to clarify the differences in genetic risk factors by age at onset (AAO). The early-onset group (AAO

To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan Retrospective multicenter study In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions. The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region. We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.

Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is RPS19 [NM...

Treacher Collins syndrome (TCS) is a heterogenous malformation syndrome characterized by a distinct facial appearance including downslanting palpebral fissures, malar hypoplasia, conductive hearing loss, and mandibular hypoplasia. Recently, a new causative gene, POLR1B, encoding DNA-directed RNA polymerase I subunit RPA2, was identified as a fourth type of TCS (TCS4). We describe another patient with TCS4 caused by a recurrent POLR1B variant, c.3007C>T; p.Arg1003Cys. Including our patient, all 4 patients with p.(Arg1003Cys) had atresia of the external auditory canal and microtia. All of the reported pathogenic variants in POLR1B were clustered at only 2 residues. Our patient highlights the genotype-phenotype correlation in TCS4 associated with POLR1B.

To examine the evidence for Familial Barrett’s Esophagus and Esophageal Adenocarcinoma and putative causative genes. Recent large population studies continue to provide evidence for Familial Barrett’s Esophagus and Esophageal Adenocarcinoma. Also, based on sequencing of two multigenerational families with Barrett’s esophagus and/or esophageal adenocarcinoma, two new possible causative gene variants have been identified including VSIG10L and MSX1. Familial Barrett’s esophagus and esophageal adenocarcinoma is increasingly becoming more recognized. Current guidelines also now incorporate family history as a risk factor for Barrett’s esophagus. Recent studies include DNA sequencing of multigenerational families in addition to previously performed GWAS studies. Several new gene variants now have been identified; however, phenotypic and mechanistic studies need to be performed to demonstrate their association with Barrett’s esophagus and esophageal adenocarcinoma.

Background Joubert syndrome (OMIM 213300) is an autosomal recessive disorder with gene heterogeneity. Causal genes and their variants have been identified by sequencing or other technologies for Joubert syndrome subtypes. Case presentation A two-year-old boy was diagnosed with Joubert syndrome by global development delay and molar tooth sign of mid-brain. Whole exome sequencing was performed to detect the causative gene variants in this individual, and the candidate pathogenic variants were verified by Sanger sequencing. We identified two pathogenic variants (NM_006346.2: c.1147delC and c.1054A > G) of PIBF1 in this Joubert syndrome individual, which is consistent with the mode of autosomal recessive inheritance. Conclusion In this study, we identified two novel pathogenic variants in PIBF1 in a Joubert syndrome individual using whole exome sequencing, thereby expanding the PIBF1 pathogenic variant spectrum of Joubert syndrome.

Background: Self-limited (familial) infantile epilepsy (S(F)IE), formerly known as benign (familial) infantile convulsions (13(F)1C), is an infantile cluster epilepsy with in rule a complete recovery. This form of epilepsy is most often caused by variations in the PRRT2 gene (OMIM #605751). Aim: To describe the clinical and genetic spectrum of sudden onset clusters of focal seizures in infancy. Methods: We retrospectively reviewed all individuals, who presented with unprovoked infantile seizures and selected all infants who had unprovoked clustered focal seizures between 1 and 20 months of age. We described the clinical and genetic spectrum of this cohort. Results: The data of 23 patients from 21 families were collected. All had an initial diagnosis of S(F)IE which was adjusted in 5 individuals. In 12 individuals a pathogenic variation in PRRT2 gene or complete deletion was identified. Pathogenic variants in PCDHI9 and KCNQ2 were found in respectively 3 and 1 individuals. One individual had a non-pathogenic variant in ATP1A3 and in 6 others no variants were identified. The mean cluster duration was 2.9 days (range 1-13) (see Table 1). Twelve infants had only one cluster. All patients had focal motor or non-motor seizures, in 12 (52%) followed by bilateral (tonic) clonic seizures. Positive family history was present in 74% of individuals. In 11/12 (92%) tested families, >= 1 family member carried the pathogenic PRRT2 variant. Age of seizure onset (ASO) averaged 6.2 months (range 2-20 months). Age of latest seizure averaged 16 months (range 2-92). In several interictal EEG (electroencephalogram) recordings multifocal spikes or spike-wave abnormalities were detected. Ictal EEG recordings detected primary focal abnormalities. Conclusion: We described 23 individuals with unprovoked cluster(s) of focal seizures at infancy. It appears to be a heterogeneous group. Half of them had a pathogenic variation in PRRT2 gene. Most had only one cluster of seizures. When clusters reoccur frequently, when seizures are more therapy-resistant and when seizures persist beyond the age of 2 years, another diagnosis or causative gene is likely. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Autosomal recessive inheritance pattern in a case of hereditary optic atrophy is uncommon. Patients with recessive optic atrophy without involvement of any other system are rare. There is no causative gene or genetic mutation associated with it. Here we report a case of a 16-year-old girl which was diagnosed to be a case of AROA. Genetic analysis done in this patient revealed G15043A mutation. Identification of similar cases of the AROA can increase our understanding of the disorder and formulate treatment options. Keywords: Autosomal recessive optic atrophy, Hereditary optic atrophy, G15043A mutation.

Polyglutamine (polyQ) ataxias are a heterogenous group of neurological disorders all caused by an expanded CAG trinucleotide repeat located in the coding region of each unique causative gene. To date, polyQ ataxias encompass six disorders: spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 and account for a larger group of disorders simply known as polyglutamine disorders, which also includes Huntington’s disease. These diseases are typically characterised by progressive ataxia, speech and swallowing difficulties, lack of coordination and gait, and are unfortunately fatal in nature, with the exception of SCA6. All the polyQ spinocerebellar ataxias have a hallmark feature of neuronal aggregations and share many common pathogenic mechanisms, such as mitochondrial dysfunction, impaired proteasomal function, and autophagy impairment. Currently, therapeutic options are limited, with no available treatments that slow or halt disease progression. Here, we discuss the common molecular and clinical presentations of polyQ spinocerebellar ataxias. We will also discuss the promising antisense oligonucleotide therapeutics being developed as treatments for these devastating diseases. With recent advancements and therapeutic approvals of various antisense therapies, it is envisioned that some of the studies reviewed may progress into clinical trials and beyond.

Bone mineral density (BMD) is a complex and highly hereditary trait that can lead to osteoporotic fractures. It is estimated that BMD is mainly affected by genetic factors (about 85%). BMD has been reported to be associated with both common and rare variants, and numerous loci related to BMD have been identified by genome-wide association studies (GWAS). We systematically integrated expression quantitative trait loci (eQTL) data with GWAS summary statistical data. We mainly focused on the loci, which can affect gene expression, so Summary data-based Mendelian randomization (SMR) analysis was implemented to investigate new genes and loci associated with BMD. We identified 12,477 single-nucleotide polymorphisms (SNPs) regulating 564 genes, which are associated with BMD. The genetic mechanism we detected could make a contribution in the density of BMD in individuals and play an important role in understanding the pathophysiology of cataclasis.

The causative gene in cystic fibrosis (CF) was identified in 1989, 3 years before the publication of the first issue of Human Molecular Genetics. The cystic fibrosis transmembrane conductance regulator (CFTR) gene was among the first underlying a common inherited disorder to be cloned, and hence, its subsequent utilization toward a cure for CF provides a roadmap for other monogenic diseases. Over the past 30 years, the advances that built upon knowledge of the gene and the CFTR protein to develop effective therapeutics have been remarkable, and yet, the setbacks have also been challenging. Technological progress in other fields has often circumvented the barriers. This review focuses on key aspects of CF diagnostics and current approaches to develop new therapies for all CFTR mutations. It also highlights the major research advances that underpinned progress toward treatments and considers the remaining obstacles.

TMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (DFNA36) and autosomal recessive non-syndromic hearing loss (DFNB7/11). To date, 125 pathogenic variants in TMC1 have been reported. Most of the TMC1 variants are responsible for autosomal recessive hearing loss, with only 7 variants reported as causative for DFNA36. Here we reported the prevalence of TMC1-associated hearing loss in a large non-syndromic hearing loss cohort of about 12,000 subjects. As a result, we identified 26 probands with TMC1-associated hearing loss and the estimated prevalence of TMC1-associated hearing loss in the Japanese hearing loss cohort to be 0.18% among all patients. Among the 26 probands with TMC1-associated hearing loss, 15 cases were identified from autosomal dominant hearing loss families. By using the audiometric data from the probands, family members and previously reported cases, we evaluated the hearing deterioration speed for DFNA36 patients. In addition, we performed haplotype analysis for 11 unrelated autosomal dominant hearing loss families carrying the same variant TMC1: NM_138691:c.1627G > A:p.D543N. The results clearly indicated that the same haplotype was present despite of families being unrelated, supporting the contention that this variant occurred by founder mutation.

Mesomelic dysplasia (MD) encompasses a heterogeneous group of disorders characterized by shortening of the middle segments of the limbs. Previous studies have revealed the development of Nievergelt type-like MD accompanied by postaxial toe reduction in a patient with a ~500 kb microdeletion at 2q11.2 involving AFF3 alone, and the occurrence of Nievergelt type-like MD in mice with a ~353 kb deletion involving Aff3, together with strong expression of mouse Aff3 in the developing limbs and zeugopod. We encountered a 2 6/12-year-old Japanese girl with an unclassifiable MD associated with hypoplasia of postaxial toes, and identified a de novo likely pathogenic variant of AFF3 (NM_002285.2:c.697 G > A, p.(Ala233Thr)) by whole exome sequencing. The results provide further evidence for AFF3 being the causative gene for MD with foot malformation which may be termed "AFF3-related MD" or "Steichen-Gersdorf type MD".

Background: Recently, comprehensive genetic approaches for steroid-resistant nephrotic syndrome (SRNS) using next-generation sequencing (NGS) have been established, but causative gene mutations could not be detected in almost 70% of SRNS patients. Main reason for the low variant detection rate is that most of them are SRNS caused not by genetic but by immunological factors. But some of them are probably because of the difficulty of detecting copy number variations (CNVs) in causative genes by NGS. Methods: In this study, we performed two analytical methods of NGS data-dependent pair analysis and custom array comparative genomic hybridization (aCGH) in addition to NGS analysis in an infantile nephrotic syndrome case. Results: We detected only one known pathogenic heterozygous missense mutation in exon 7 of COQ6 c.782C > T, p.(Pro261Leu) by NGS. With pair analysis, heterozygous exon 1–2 deletion was suspected and was confirmed by custom aCGH. As a result, a small CNV was successfully detected in the COQ6 gene. Because we could detect variants in COQ6 and could start treatment by coenzyme Q10 (CoQ10) in his very early stage of SRNS, the patient achieved complete remission. Conclusions: These relatively novel methods should be adopted in cases with negative results in gene tests by NGS analysis. Especially, in cases with CoQ10 deficiency, it is possible to delay initiating dialysis by starting treatment at their early stages.

Hereditary bowel tumours are usually part of a distinct syndrome which require management of both intestinal and extra-intestinal disease. Polyposis syndromes include: Familial adenomatous polyposis, MUTYH-associated polyposis, Serrated polyposis syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome and PTEN-hamartomatous syndromes. Of all colorectal cancers (CRC), 5%–10% will be due to an underlying hereditary CRC syndrome. Diagnosis and management of polyposis syndromes is constantly evolving as new scientific and technological advancements are made with respect to identifying causative genes and increased sophistication of endoscopic therapy to treat polyps. This, in addition to data yielded from meticulous record-keeping by polyposis registries has helped to guide management in what are otherwise relatively rare conditions. These data help guide clinical management of patients and their ‘at-risk’ relatives. Diagnosis is both genetic where possible but clinical recognition is key in the absence of an identifiable causative gene. Furthermore, some syndromes can overlap which can additionally complicate diagnosis. The principle goals of polyposis management are first to manage and treat the presenting patient and then to identify ‘at-risk’ patients, through screening and predictive genetic testing, endoscopic surveillance to allow therapy and guide surgical prophylaxis. Due to the complexity of diagnosis and management, patients and their families should be referred to a genetics centre or a polyposis registry where dedicated management can take place.

Paired-like homeobox (PHOX)2B is considered to be the causative gene of congenital central hypoventilation syndrome (CCHS), a dominant genetic disorder that results in abnormal central respiratory ...

The term epidermolysis bullosa (EB) refers to a group of hereditary skin blistering diseases. The group is clinically and genetically heterogeneous, but all EB forms are associated with mechanically induced skin blistering and fragility. The causative gene mutations of most EB types are known. The current international consensus classification contains four main types: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome (KS). The classification is based on the morphological level of blister formation. In EBS, the split is intra-epidermal, in JEB along the basement membrane and in DEB below the basement membrane. In Kindler syndrome, the dermal-epidermal junction is disorganized, and blisters can occur on all three levels. Each major EB type has further subtypes which may differ in terms of their genetic, biological or clinical characteristics. Traditionally, EB treatments have been symptomatic, but increasing understanding of disease etio-pathogenesis is facilitating development of novel evidence-based therapy approaches. First gene- and cell-based therapies are being tested at preclinical level and in clinical trials. New knowledge on secondary disease mechanisms has led to development and clinical testing of urgently needed symptom-relief therapies using small molecules and biologicals.

BackgroundKCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.MethodsIndividuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.ResultsWe identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.ConclusionThese findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.

Background and Purpose: Deletion of Endoglin (Eng), an arteriovenous malformation (AVM) causative gene causes AVM in the brain angiogenic region. Reduction of pericytes is correlate with brain AVM hemorrhage. The platelet-derived growth factor B and its receptor β (PDGF-B/PDGFRβ) play important roles in regulating pericyte recruitment during angiogenesis. We hypothesize that mutation of PDGFRβ causes cerebrovascular malformation and enhances bAVM severity in Eng mutant mice. Methods: Three mouse models were used: (1) Pdgfrβ F7 (F7) mice that have mutations disrupting Pdgfrβ signaling, (2) Pdgfb -icreER; Eng f /f mice that have Pdgfb promoter driving, tamoxifen (TM) inducible cre expression in ECs and an floxed Eng gene; and (3) Pdgfb -icreER; Eng f /f ;F7 +/- mice. Brain angiogenesis was induced by intra-brain injection of an adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF). Brain AVMs were induced in Pdgfb -icreER; Eng f /f and Pdgfb -icreER; Eng f /f ;F7 mice by TM induced EC Eng deletion and intra-brain AAV-VEGF injection. Brain AVM phenotypes were analyzed 8-weeks after model induction by latex vascular cast to detect arteriovenous shunts and macroscopic level of AVMs, immunostaining and Prussian blue staining to quantify dysplasia vessels and hemorrhage. Results: Compared to WT mice, F7 +/- and F7 +/+ mice have more dysplastic vessels and fewer vascular pericyte before and after AAV-VEGF injection. F7 +/- and F7 +/+ mice showed hemorrhage on the AAV-VEGF injection sites and AVM like vessels (a few arteriovenous shunts) in 16% F7 +/- and 66% of F7 +/+ mice. Pdgfb -icreER; Eng f /f mice showed dysplastic vessels and hemorrhage at AAV-VEGF injection sites. Compared to Pdgfb -icreER; Eng f /f mice, Pdgfb -icreER; Eng f /f ;F7 +/- had a higher penetrance of bAVM (71% vs 50%) and more dysplastic vessels. Conclusion: F7 mutation cause AVM like structure in mouse brain and exacerbates bAVM phenotype in Eng mutant mice.

MAMLD1 (alias CXorf6) was first documented in 2006 as a causative gene of 46,XY differences/disorders of sex development (DSD). MAMLD1/Mamld1 is expressed in the fetal testis and is predicted to enhance the expression of several Leydig cell-specific genes. To date, hemizygous MAMLD1 variants have been identified in multiple 46,XY individuals with hypomasculinized external genitalia. Pathogenic MAMLD1 variants are likely to cause genital abnormalities at birth and are possibly associated with age-dependent deterioration of testicular function. In addition, some MAMLD1 variants have been identified in 46,XX individuals with ovarian dysfunction. However, recent studies have raised the possibility that MAMLD1 variants cause 46,XY DSD and ovarian dysfunction as oligogenic disorders. Unsolved issues regarding MAMLD1 include the association between MAMLD1 variants and 46,XX testicular DSD, gene-gene interactions in the development of MAMLD1-mediated DSD, and intracellular functions of MAMLD1.

Although NDNF was recently reported as a novel causative gene for congenital hypogonadotropic hypogonadism (CHH), this conclusion has yet to be validated. In this study, we sequenced NDNF in 61 Japanese CHH patients. No variants, except for nine synonymous substitutions that appear to have no effect on splice-site recognition, were identified in NDNF coding exons or flanking intronic sequences. These results indicate the rarity of NDNF variants in CHH patients and highlight the genetic heterogeneity of CHH.

Leucine-rich repeat kinase 2 (LRRK2) is a causative gene product of autosomal-dominant Parkinson's disease and has been shown to play a role in lysosomal regulation. We have previously shown that endogenous LRRK2 recruited its substrates Rab8a and Rab10 onto overloaded lysosomes depending on their phosphorylation, which functioned in the suppression of lysosomal enlargement as well as the promotion of the exocytic release of lysosomal cathepsins. In this chapter, we introduce two methods to analyze cellular functions of LRRK2 upon exposure to lysosomal overload stress in RAW264.7 cells.

Rare recessive diseases are difficult to study for one obvious reason: they are rare. It can be challenging to identify a sufficient number of cases to properly characterize a disease phenotype and subsequently identify the causative gene. Nevertheless, the quest to identify genes associated with human phenotypes, especially rare genetic diseases, has been a primary goal of genetic researchers for decades. The identification of rare disease-associated genes in humans has been greatly facilitated by the study of unusual clusters of disease, such as multiple affected members of the same family or multiple families with affected children within a special population. This chapter will define autosomal recessive inheritance, examine its role in rare pediatric disease, and review the historical contributions of founder populations and consanguineous families in unraveling the association between a rare disease and its causative gene.

International audience; Achondroplasia is the most common form of human dwarfism. The molecular basis of achondroplasia was elucidated in 1994 with the identification of the fibroblast growth factor receptor 3 (FGFR3) as the causative gene. Missense mutations causing achondroplasia result in activation of FGFR3 and its downstream signaling pathways, disturbing chondrogenesis, osteogenesis, and long bone elongation. A more accurate understanding of the clinical and molecular aspects of achondroplasia has allowed new therapeutic approaches to be developed. These are based on: clear understanding of the natural history of the disease; proof-of-concept preclinical studies in mouse models; and the current state of knowledge regarding FGFR3 and related growth plate homeostatic pathways. This review provides a brief overview of the preclinical mouse models of achondroplasia that have led to new, non-surgical therapeutic strategies being assessed and applied to children with achondroplasia through pioneering clinical trials.

Background Recently hyperphenylalaninemia (HPA) caused by variants in DNAJC12 was reported and this suggested a new strategy for diagnosis. But DNAJC12‐associated HPA is a rare in Chinese population so far. Methods The clinical information and blood samples from the patient and his family members were collected and analyzed. Whole‐exome sequencing (WES) was used to identify the causative gene. Results We reported a newborn patient with HPA, having excluded the causes in common genes associated with HPA. By using whole‐exome sequencing, novel compound heterozygosity mutations in DNAJC12 were found, namely c.306C>G (p.His102Gln) and c.182delA (p.Lys61Argfs*6). Administering a diet with low phenylalanine combined with tetrahydrobiopterin and neurotransmitter precursors were shown to be effective in preventing neurodevelopmental delay for these patients. Conclusion Our finding confirms the diagnosis of DNAJC12‐associated HPA and suggests that genetic detection of DNAJC12 should be considered when newborn screening results are positive for HPA., By using whole‐exome sequencing, we found novel compound heterozygosity mutations in DNAJC12, namely c.306C>G (p.His102Gln) and c.182delA (p.Lys61Argfs*6), which were considered to be the genetic cause of a patient with hyperphenylalaninemia.

PRDM12 is a newly identified causative gene for a type of congenital insensitivity to pain disorder, which is characterized by the inability to perceive pain. Here, we discuss the (patho)physiology of PRDM12 function and the opportunities and challenges those data provide for novel therapeutic approaches in various pain disorders.

Centronuclear myopathies (CNM) are a group of rare inherited muscular disorders leading to a significantly reduced quality of life and lifespan. To date, CNM epidemiologic reports provide limited incidence and prevalence data. Here, an integrated model utilizing available literature is proposed to obtain a better estimate of overall CNM patient numbers by age, causative gene, severity and geographic region. This model combines published epidemiology data and extrapolates limited data over CNM subtypes, resulting in patient numbers related to age and disease subtype. Further, the model calculates a CNM incidence twofold the current estimates. The estimated incidence of 17 per million births for severe X-linked myotubular myopathy (XLMTM), the main subtype of CNM, corresponds to an estimated prevalence of 2715 in the US, 1204 in the EU, 688 in Japan and 72 in Australia. In conclusion, the model provides an estimate of the CNM incidence, prevalence and survival, and indicates that the current estimates do not fully capture the true incidence and prevalence. With rapid advances in genetic therapies, robust epidemiologic data are needed to further quantify the reliability of incidence, prevalence and survival rates for the different CNM subtypes.