SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.

BACKGROUND: Otosclerosis is a common cause of adult-onset progressive hearing loss, affecting 0.3%-0.4% of the population. It results from dysregulation of bone homeostasis in the otic capsule, most commonly leading to fixation of the stapes bone, impairing sound conduction through the middle ear. Otosclerosis has a well-known genetic predisposition including familial cases with apparent autosomal dominant mode of inheritance. While linkage analysis and genome-wide association studies suggested an association with several genomic loci and with genes encoding structural proteins involved in bone formation or metabolism, the molecular genetic pathophysiology of human otosclerosis is yet mostly unknown. METHODS: Whole-exome sequencing, linkage analysis, generation of CRISPR mutant mice, hearing tests and micro-CT. RESULTS: Through genetic studies of kindred with seven individuals affected by apparent autosomal dominant otosclerosis, we identified a disease-causing variant in SMARCA4, encoding a key component of the PBAF chromatin remodelling complex. We generated CRISPR-Cas9 transgenic mice carrying the human mutation in the mouse SMARCA4 orthologue. Mutant Smarca4+/E1548K mice exhibited marked hearing impairment demonstrated through acoustic startle response and auditory brainstem response tests. Isolated ossicles of the auditory bullae of mutant mice exhibited a highly irregular structure of the incus bone, and their in situ micro-CT studies demonstrated the anomalous structure of the incus bone, causing disruption in the ossicular chain. CONCLUSION: We demonstrate that otosclerosis can be caused by a variant in SMARCA4, with a similar phenotype of hearing impairment and abnormal bone formation in the auditory bullae in transgenic mice carrying the human mutation in the mouse SMARCA4 orthologue.

Classification of PTEN germline non-truncating variants: a new approach to interpretation.

BACKGROUND: PTEN hamartoma tumour syndrome (PHTS) encompasses distinct syndromes, including Cowden syndrome resulting from PTEN pathogenic variants. Missense variants account for 30% of PHTS cases, but their classification remains challenging. To address these difficulties, guidelines were published by the Clinical Genome Resource PTEN Variant Curation Expert Panel. METHODS: Between 2010 and 2020, the Bergonie Institute reference laboratory identified 76 different non-truncating PTEN variants in 166 patients, 17 of which have not previously been reported. Variants were initially classified following the current guidelines. Subsequently, a new classification method was developed based on four main criteria: functional exploration, phenotypic features and familial segregation, in silico modelling, and allelic frequency. RESULTS: This new method of classification is more discriminative and reclassifies 25 variants, including 8 variants of unknown significance. CONCLUSION: This report proposes a revision of the current PTEN variant classification criteria which at present rely on functional tests evaluating only the phosphatase activity of PTEN and apply a particularly stringent clinical PHTS score.The classification of non-truncating variants of PTEN is facilitated by taking into consideration protein stability for variants with intact phosphatase activity, clinical and segregation criteria adapted to the phenotypic variability of PHTS and by specifying the allelic frequency of variants in the general population. This novel method of classification remains to be validated in a prospective cohort.

Evidence of a genetic background predisposing to complex regional pain syndrome type 1.

BACKGROUND: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. METHODS: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed. RESULTS: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. CONCLUSION: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.

A comparative medical genomics approach may facilitate the interpretation of rare missense variation.

PURPOSE: To determine the degree to which likely causal missense variants of single-locus traits in domesticated species have features suggestive of pathogenicity in a human genomic context. METHODS: We extracted missense variants from the Online Mendelian Inheritance in Animals database for nine animals (cat, cattle, chicken, dog, goat, horse, pig, rabbit and sheep), mapped coordinates to the human reference genome and annotated variants using genome analysis tools. We also searched a private commercial laboratory database of genetic testing results from >400 000 individuals with suspected rare disorders. RESULTS: Of 339 variants that were mappable to the same residue and gene in the human genome, 56 had been previously classified with respect to pathogenicity: 31 (55.4%) pathogenic/likely pathogenic, 1 (1.8%) benign/likely benign and 24 (42.9%) uncertain/other. The odds ratio for a pathogenic/likely pathogenic classification in ClinVar was 7.0 (95% CI 4.1 to 12.0, p<0.0001), compared with all other germline missense variants in these same 220 genes. The remaining 283 variants disproportionately had allele frequencies and REVEL scores that supported pathogenicity. CONCLUSION: Cross-species comparisons could facilitate the interpretation of rare missense variation. These results provide further support for comparative medical genomics approaches that connect big data initiatives in human and veterinary genetics.

BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.

INTRODUCTION: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome. METHODS: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein. RESULTS: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures. CONCLUSION: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.

Phenotype-genotype spectrum of a cohort of congenital muscular dystrophies: a single-centre experience from India.

Congenital Muscular Dystrophies (CMD) are phenotypically and genotypically heterogenous disorders with a prevalence of 0.68 to 2.5/100,000, contributing to significant morbidity and mortality. We aimed to study the phenotype-genotype spectrum of genetically confirmed cases of CMD. This was retrospective & descriptive study done at a quaternary care referral centre in south India. Genetically confirmed cases of CMDs seen between 2010 to 2020 were recruited. Detailed clinical history, including pedigree, MRI brain/muscle, next generation sequencing results of 61 CMD cases were collected. Collagen VI-related dystrophy (COL6-RD) (36%) was the most common subtype with variants frequently seen in COL6A1 gene. Other CMDs identified were LAMA2-RD (26%), alpha-dystroglycan-RD (19%), LMNA-RD (8%), CHKB-RD (7%) and SEPN1-RD (3%). Similar to previous cohorts, overall, missense variants were common in COL-6 RD. Variants in triple helical domain (THD) of COL6-RD were seen in 11/22 patients, 5 of whom were ambulatory contrary to previous literature citing severe disease with these variants. However, our follow-up period was shorter. In the LAMA2-RD, 2/16 patients were ambulatory & all 16 carried truncating variants. Among dystroglycanopathies, FKRP-RD was the commonest. Milder phenotype of FKRP- RD was observed with variant c.1343C > T, which was also a recurrent variant in our cohort. p.Arg249Trp variant in LMNA-CMD associated with early loss of ambulation was also identified in 1/5 of our patients who expired at age 2.8 years. The current retrospective series provides detailed clinical features and mutation patterns of genetically confirmed cases of CMD from a single center in India.

TP53 c.455C>T p.(Pro152Leu) pathogenic variant is a lower risk allele with attenuated risks of breast cancer and sarcoma.

Germline (likely) pathogenic TP53 variants cause Li-Fraumeni syndrome (LFS), typically associated with sarcoma, brain, breast and adrenal tumours. Although classical LFS is highly penetrant, the p.R337H variant, common in Brazil, is typically associated with childhood adrenal tumours and an older onset age of other LFS tumours. Previously, we reported the finding of p.P152L in 6 children from 5 families with adrenal tumours. We have now assessed cancer risks over the subsequent 23 years, and in one further family with p.P152L. Cancer risks were compared with those in the 11 families known to our service with classical dominant negative mutations affecting neighbouring codons 245 and 248 (codon 245/248).Compared with codon 245/248 families, we found lower age-related risks for all non-adrenal tumours in codon 152 families (p<0.0001) with an absence of breast cancer as compared with 100% penetrance by age 36 years in codon 245/248 families (p<0.0001), and lower rates of sarcoma in non-irradiated individuals (p=0.0001). Although there were more adrenal tumours in codon 152 families (6/26 individuals, 1/27 for codon 245/248), this was not significant (p=0.05).Understanding codon-specific cancer risks in LFS is important for accurate personalised cancer risk assessment, and subsequent prevention and early detection strategies.

Pseudocoloboma-like maculopathy with biallelic RDH12 missense mutations.

BACKGROUND: Hereditary maculopathy is a group of clinically and genetically heterogeneous disorders. With distinctive clinical features, subtypes of macular atrophy may correlate with their genetic defects. METHODS: Seven patients from six families with adolescent/adult-onset maculopathy were examined in this clinical case series. A detailed medical history and eye examination were performed. Genomic DNA sequencing was performed using whole exome sequencing or direct sequencing of retinol dehydrogenase 12 (RDH12) coding exons. RESULTS: Seven patients, including one male and six female patients, with pseudocoloboma-like maculopathy had biallelic missense RDH12 mutations. The most common mutant allele found in six of the seven patients was p.Ala269Gly. The average disease onset was at age 19.3 years, and visual acuity ranged from count fingers to 1.0. Most of the patients had mild myopic refraction. Common findings on fundus examination and spectral-domain optical coherence tomography include discrete margins of pseudocoloboma-like macular lesions with variable degrees of chorioretinal atrophy, excavation of retinal tissue and pigmentary changes mainly in the macular area. The electroretinograms were relatively normal to subnormal in all participants. CONCLUSIONS: Progressive macular degeneration with a relatively normal peripheral retina and subsequent development of a pseudocoloboma-like appearance were the main clinical features in patients with compound heterozygous RDH12 missense mutations. Genetic testing may be crucial for early diagnosis and may play a key role in the development of future treatment strategies.

Gain-of-function p.F28S variant in RAC3 disrupts neuronal differentiation, migration and axonogenesis during cortical development, leading to neurodevelopmental disorder.

BACKGROUND: RAC3 encodes a Rho family small GTPase that regulates the behaviour and organisation of actin cytoskeleton and intracellular signal transduction. Variants in RAC3 can cause a phenotypically heterogeneous neurodevelopmental disorder with structural brain anomalies and dysmorphic facies. The pathomechanism of this recently discovered genetic disorder remains unclear. METHODS: We investigated an early adolescent female with intellectual disability, drug-responsive epilepsy and white matter abnormalities. Through exome sequencing, we identified the novel de novo variant (NM_005052.3): c.83T>C (p.Phe28Ser) in RAC3. We then examined the pathophysiological significance of the p.F28S variant in comparison with the recently reported disease-causing p.Q61L variant, which results in a constitutively activated version of RAC3. RESULTS: In vitro analyses revealed that the p.F28S variant was spontaneously activated by substantially increased intrinsic GTP/GDP-exchange activity and bound to downstream effectors tested, such as PAK1 and MLK2. The variant suppressed the differentiation of primary cultured hippocampal neurons and caused cell rounding with lamellipodia. In vivo analyses using in utero electroporation showed that acute expression of the p.F28S variant caused migration defects of excitatory neurons and axon growth delay during corticogenesis. Notably, defective migration was rescued by a dominant negative version of PAK1 but not MLK2. CONCLUSION: Our results indicate that RAC3 is critical for brain development and the p.F28S variant causes morphological and functional defects in cortical neurons, likely due to the hyperactivation of PAK1.

De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.

OBJECTIVE: To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. METHODS: Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. RESULTS: LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. CONCLUSION: These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.

Pre-implantation genetic diagnosis in an Iranian family with a novel mutation in MUT gene.

BACKGROUND: Methylmalonic acidemia (MMA), which is an autosomal recessive metabolic disorder, is caused by mutations in methylmalonyl-CoA mutase (MUT) gene. As a result, the conversion of methylmalonyl-CoA to succinyl-CoA is impaired in this disorder, leading to a wide range of clinical manifestations varying from no signs or symptoms to severe lethargy and metabolic crisis in newborn infants. Since identification of novel mutations in MUT gene can help discover the exact pathogenesis of MMA and also use these disease-causing mutations in prenatal diagnosis, this study was conducted to uncover the possible mutations in an Iranian couple with a deceased offspring clinically diagnosed as having organic acidemia. Moreover, to prevent the occurrence of the mutation in the next pregnancy, we took the advantage of pre-implantation genetic diagnosis (PGD), which resulted in a successful pregnancy. CASE PRESENTATION: The affected individual was a 15-month-old boy who passed away due to aspiration pneumonia. The child presented at the age of 3 months with lethargy, protracted vomiting, hypotonia, and decreased level of consciousness. To find the mutated gene, Next Generation Sequencing (NGS) was performed as carrier testing for the parents and the results revealed a novel (private) heterozygous missense mutation in MUT gene (c.1055A > G, p.Q352R). After performing PGD on three blastomeres, one was identified as being homozygous wild-type that was followed by successful pregnancy. CONCLUSIONS: Our study identified a novel, deleterious, heterozygous missense mutation in MUT gene in a couple and helps to consider the genetic counselling and prenatal diagnosis more seriously for this family with clinical phenotypes of organic acidemia.

Variants of uncertain significance in BRCA testing: evaluation of surgical decisions, risk perception, and cancer distress.

Studies suggest that patients carrying a BRCA variant of uncertain significance (VUS) may have lingering confusion concerning results interpretation. Counseling for uninformative BRCA-negative (UN) results is thought to be more straightforward, despite the fact that both results lead to similar methods of empiric cancer risk counseling. This study compared surgical choices and perceptions between 71 patients with VUS results and 714 patients with UN results. All patients underwent genetic counseling because of a personal or family history of breast or ovarian cancer between 1997 and 2010, and completed a 2-year follow-up survey. Risk-reducing mastectomy rates in both groups were 7% (p = 1.00) and risk-reducing oophorectomy rates were 5% and 3%, respectively (p = 0.42). The VUS group reported less cancer distress reduction than the UN group (23.0% vs 35.8%, respectively, p = 0.043). Over 90% of both groups found the counseling process helpful. Overall, the study suggests that VUS results disclosed in genetic counseling did not cause excessive surgery or exaggerated cancer distress, though patients with a VUS found counseling somewhat less informative or reassuring. Future research on communication of VUS results, including pre-and post-test counseling, is essential for full realization of the potential for genomic medicine.

Compound Heterozygous Factor VII Deficiency c.1025G>A p.(Arg342Gln) With Novel Missense Variant c.194C>G p.(Ala65Gly).

Factor VII (FVII) deficiency manifests as prolonged prothrombin time (PT) and reduced FVII activity. We report a case of an asymptomatic 60-year-old gentleman with discrepancies in PT and FVII coagulant activity levels (FVII:C) on three different thromboplastin reagents used. Further sequence analysis on genomic DNA showed double heterozygosity for c.1025G>A p.Arg342Gln and c.194C>G p.Ala65Gly in the F7 gene. To date, p.Ala65Gly in exon 2 of the F7 gene represents a novel variant in patients with FVII deficiency and is classified as likely pathogenic. Computational prediction tools support a deleterious effect on the gene. The genotype-phenotype association and the clinical significance of this exon 2 missense variant is proposed in this case report.

A Missense Mutation in TRPS1 in a Family with Trichorhinophalangeal Syndrome Type III Accompanied by Ankylosing Spondylitis.

Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterized by distinctive craniofacial features, skeletal abnormalities and short stature; it is classified into three subtypes according to genetics and clinical manifestations. We report a Han Chinese family with 2 TRPS type III patients, the proband and his mother, with typical clinical presentation. There were also 3 ankylosing spondylitis (AS) patients in this family, the proband's mother and 2 uncles. A missense mutation, c.2762G>A (p.Arg921Gln), in the transcriptional repressor GATA binding 1 (TRPS1) gene was detected in the proband and his mother. The association between TRPS and AS and the diagnostic criteria for TRPS are discussed.

Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro / Experiência de vida-real com inotersena no CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro

Abstract Background Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype. Objective To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN). Methods Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1-first dose of inotersen). Disease progression was evaluated by standard measures. Results Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted. Conclusion The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.

Resumo Antecedentes Amiloidose hereditária por transtirretina (ATTRv) é uma doença hereditária, progressiva e fatal ainda largamente subdiagnosticada. Mutações no gene transtirretina (TTR) promovem desestabilização, desdobramento, agregação e depósito da proteína TTR em tecidos do corpo, o que faz da ATTRv uma doença de fenótipo clínico heterogêneo. Objetivo Descrever a eficácia e segurança da terapia com inotersena no longo prazo em pacientes com neuropatia periférica ATTRv (ATTRv-PN). Métodos Pacientes que completaram o estudo pivotal NEURO-TTR e o estudo de extensão aberta NEURO-TTR OLE migraram para este estudo e foram acompanhados por no mínimo 18 meses adicionais, em média por 67 meses, e por até 76 meses, desde o dia 1 da terapia com inotersena (D1-primeira dose de inotersena). A progressão da doença foi avaliada por medidas padronizadas. Resultados Dez pacientes com ATTRv-PN com mutação Val30Met foram incluídos. A duração média da doença no D1 era de 3 anos, e a média de idade dos pacientes era de 46,8 anos. Durante o período de acompanhamento adicional de 18 meses, a função neurológica, baseada no Neuropathy Impairment Score e no Polyneuropathy Disability Score, os aspectos de funcionalidade (Karnofsky Performance Status), nutricional e cardíacos estavam mantidos. Não se observou nenhum novo sinal de segurança. Conclusão O tratamento com inotersena foi eficaz e bem tolerado por 67 meses em média, e por até 76 meses. Nossos resultados são consistentes com os de estudos maiores de fase III.

Enfermedad neurológica asociada al gen KIF1A: correlación genotipo/fenotipo / KIF1A gene-associated neurological disease: the correlation between genotype and phenotype

Introducción: La encefalopatía KIF1A-associated-neurological-disorder (KAND) es un grupo de patologías neurodegenerativas progresivas de diversa gravedad ocasionadas por mutaciones en el gen KIF1A (kinesin family member 1A) situado en el cromosoma 2q37.3. Dicho gen codifica una proteína de la familia de las cinesinas 3 que participa en el transporte anterógrado de las vesículas presinápticas dependientes del trifosfato de adenosina a través de microtúbulos neuronales. Casos clínicos: Se describen cuatro pacientes, con edades entre 1 y 13 años, con mediana de inicio de los síntomas de cinco meses (rango intercuartílico: 0-11 meses), lo que supone una prevalencia aproximada de 1 de cada 64.000 menores de 14 años para nuestra población pediátrica. Clínicamente, destacaron discapacidad intelectual, hipotonía axial y paraparesia espástica en 4/4, y síntomas cerebelosos en 2/4. Otras manifestaciones fueron incontinencia urinaria, polineuropatía sensitivomotora y alteración conductual. Destaca, en el caso 2, la alteración en el videoelectroencefalograma, que mostraba epilepsia focal con generalización secundaria y focalidad paroxística occipitoparietal posterior derecha con transmisión contralateral. También mostraba crisis oculógiras en supraversión instantáneas pluricotidianas sin correlato electroencefalográfico. Conclusiones: En nuestra serie, la encefalopatía KAND, fenotipo trastorno neurodegenerativo con retraso global del desarrollo, de la marcha y espasticidad progresiva de los miembros inferiores, atrofia cerebelosa y/o afectación de la corteza visual, fue predominante, y en uno de los casos asoció polineuropatía sensitivomotora. La mutación de novo missense fue más frecuente y en tres casos es la primera descripción conocida. Un caso mostraba epilepsia focal y crisis oculógiras no epilépticas.(AU)

Introduction: KIF1A-associated-neurological-disorder (KAND) encephalopathy is a group of progressive neurodegenerative pathologies of varying severity caused by mutations in the KIF1A gene (Kinesin family member 1A) located on chromosome 2q37.3. This gene encodes a protein of the kinesin-3 family that participates in the ATP-dependent anterograde transport of presynaptic vesicles through neuronal microtubules. Case report: Four patients are described, aged 1-13 years, with a median onset of symptoms of 5 months (IQR 0-11 months), which represents an approximate prevalence of 1 per 64,000 children under 14 years of age for our pediatric population. Clinically, intellectual disability (ID), axial hypotonia and spastic paraparesis stood out in 4/4 and cerebellar symptoms in 2/4. Other manifestations were urinary incontinence, sensory-motor polyneuropathy, and behavioral alteration. In case 2, the alteration in the video-EEG stands out, which showed focal epilepsy with secondary generalization and right posterior occipito-parietal paroxysmal focality with contralateral transmission. She also showed instantaneous pluricotidian supraversion oculogyric seizures without EEG correlates. Conclusions: In our series, KAND encephalopathy had a predominant neurodegenerative disorder phenotype with global developmental delay, gait delay, and progressive spasticity of the lower limbs, cerebellar atrophy, and/or involvement of the visual cortex, which in one case was associated with sensory-motor polyneuropathy. The de novo missense mutation was more frequent and in three cases it is the first known description. One case showed focal epilepsy and nonepileptic oculogyric seizures.(AU)

CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders.

BACKGROUND: Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. METHODS AND RESULTS: Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A, was strongly associated with markers of n-3 fatty acid metabolism, including degree of unsaturation (P=1.16×10-34), levels of polyunsaturated fatty acids, n-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (P=2.35×10-15, P=4.02×10-19, and P=7.92×10-27). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (P=1.04×10-9). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. CONCLUSION: Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.

The Clinical and Mutational Spectrum of Turkish Patients with Cystinosis.

BACKGROUND AND OBJECTIVES: Infantile nephropathic cystinosis is a severe disease that occurs due to mutations in the cystinosis gene, and it is characterized by progressive dysfunction of multiple organs; >100 cystinosis gene mutations have been identified in multiple populations. Our study aimed to identify the clinical characteristics and spectrum of cystinosis gene mutations in Turkish pediatric patients with cystinosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We identified the clinical characteristics and spectrum of cystinosis gene mutations in Turkish patients with cystinosis in a multicenter registry that was established for data collection. The data were extracted from this registry and analyzed. RESULTS: In total, 136 patients (75 men and 61 women) were enrolled in the study. The most common clinical findings were growth retardation, polyuria, and loss of appetite. None of the patients had the 57-kb deletion, but seven novel mutations were identified. The most common mutations identified were c.681G>A (p.Glu227Glu; 31%), c.1015G>A (p.Gly339Arg; 22%), and c.18_21 del (p.Thr7Phefs*7; 14%). These mutations were associated with earlier age of disease onset than the other mutations. To understand the effects of these allelic variants on clinical progression, the mutations were categorized into two major groups (missense versus deletion/duplication/splice site). Although patients with missense mutations had a better eGFR at the last follow-up visit, the difference was not significant. Patients in whom treatment began at age <2 years old had later onset of ESRD (P=0.02). Time to ESRD did not differ between the patients with group 1 and group 2 mutations. CONCLUSIONS: The most common cystinosis gene mutations identified in Turkey were c.681G>A (p.Glu227Glu), c.1015G>A (p.Gly339Arg), and c.18_21 del (p.Thr7Phefs*7). Patients with less severe cystinosis gene mutations tend to have better kidney outcome.