Central diabetes insipidus, or arginine vasopressin deficiency (AVP-D), is a rare disorder caused by insufficient release of antidiuretic hormone from the pituitary gland. The disease is characterised by severe polyuria...Central diabetes insipidus, or arginine vasopressin deficiency (AVP-D), is a rare disorder caused by insufficient release of antidiuretic hormone from the pituitary gland. The disease is characterised by severe polyuria and polydipsia, which, in rare cases, can be caused by variants in the AVP gene. The aim of the present study was to identify the genetic cause of AVP-D in two families and compile and discuss an updated and complete catalogue of variants in AVP associated with AVP-D. Two Danish families with autosomal dominant inheritance of symptoms indicating AVP-D were included, and probands underwent an arginine-stimulated copeptin test. Genetic testing included direct sequencing of the coding regions of AVP. HGMD professional, ClinVar, and literature mining combined with expert-assisted filtering and curation were applied to compile all pathogenic variants in AVP reported until now. Genetic analysis of the two probands, both of which had abnormally low levels of arginine-stimulated copeptin, and selected family members revealed co-segregation of AVP-D and heterozygosity for a novel pathogenic missense variant in AVP (c.122G>A, p.(Cys41Tyr)). This variant was included in an updated and curated list of 110 pathogenic AVP variants associated with AVP-D. These findings expand the known mutational spectrum of AVP and provide a consolidated resource to support clinical interpretation and future genotype-phenotype studies.
Several clinical entities are associated with ACTB pathogenic variants. Most notably, constitutional missense gain-of-function variants are linked to Baraitser-Winter cerebrofrontofacial syndrome, and recurrent somatic g...Several clinical entities are associated with ACTB pathogenic variants. Most notably, constitutional missense gain-of-function variants are linked to Baraitser-Winter cerebrofrontofacial syndrome, and recurrent somatic gain-of-function Arg147 variants are reported in Becker's nevus or in smooth muscle hamartomas. We describe three individuals with mosaic hypopigmentation following Blaschko's lines, associated or not with neurodevelopmental features, with postzygotic ACTB variants identified with deep next-generation sequencing on skin biopsy from an affected area. We identified the same missense p.(Arg335His) variant in individuals #1 and #3, already reported in a constitutional state in a fetus. Individual #2 carried an unreported in-frame insertion-deletion (p.(Ser348_Leu349insPheHisLeuProProSerIle)). Thus, we describe a previously unreported phenotype related to postzygotic ACTB variants with hypopigmentation associated or not with neurodevelopmental features, distinct from Becker presentations, bridging constitutional neurodevelopmental and somatic cutaneous phenotypes.
GAA-FGF14 ataxia (spinocerebellar ataxia 27B, SCA27B), identified in 2023, is a major cause of adult-onset autosomal dominant cerebellar ataxia (ADCA). In this study, we assessed the frequency of GAA-FGF14 ataxia in a pr...GAA-FGF14 ataxia (spinocerebellar ataxia 27B, SCA27B), identified in 2023, is a major cause of adult-onset autosomal dominant cerebellar ataxia (ADCA). In this study, we assessed the frequency of GAA-FGF14 ataxia in a predominantly sporadic German cohort of 107 genetically unresolved index patients using long-range PCR and nanopore sequencing. Somatic mosaicism of GAA repeat length was assessed using a custom bioinformatics pipeline based on a modified cyclic Smith-Waterman algorithm. This approach provided streamlined detection and enabled precise genotyping. Among sporadic cases, 10% had a pathogenic and 6% an intermediate repeat expansion. Across the entire cohort, 13% carried a pathogenic and 5% an intermediate repeat expansion. Diagnostic yield varied substantially by clinical presentation: 50% in cases with typical GAA-FGF14-ataxia features, 13% in patients with compatible but less characteristic features and 5% in atypical presentations. In conclusion, this study further corroborates existing evidence that GAA-FGF14 ataxia is a frequent cause of both sporadic and familial cerebellar ataxia. Given its high diagnostic yield and the limited detectability by standard short-read genome sequencing, targeted testing should be more widely implemented.
Biallelic loss-of-function variants in FIG4 are associated with Charcot-Marie-Tooth disease type 4J, a progressive peripheral sensorimotor demyelinating polyneuropathy. Biallelic null FIG4 variants cause Yunis-Varon synd...Biallelic loss-of-function variants in FIG4 are associated with Charcot-Marie-Tooth disease type 4J, a progressive peripheral sensorimotor demyelinating polyneuropathy. Biallelic null FIG4 variants cause Yunis-Varon syndrome, a severe neurological disorder characterized by global developmental delay, hypotonia, brain malformations, skeletal defects, dysmorphic facial features, and juvenile lethality. In the past few years, many individuals with combined central and peripheral nervous system disease associated with biallelic FIG4 variants have been described. In addition, certain heterozygous FIG4 variants are associated with amyotrophic lateral sclerosis. We describe an individual with global developmental delay, hypotonia, cerebral hypomyelination, peripheral hypomyelinating polyneuropathy, frequent fractures, and juvenile ossifying fibroma. The spectrum of clinical presentation of FIG4-related disorders is increasingly being recognized. Our observations expand the phenotypic spectrum of FIG4-related neurological disorders. In addition, we provide an overview of the potential genotype-phenotype correlations of this expanding group of disorders of lysosomal homeostasis.
Primary hereditary microcephaly (MCPH) comprises a group of genetically heterogeneous disorders characterized by severe microcephaly and mild intellectual disability. It differs from syndromic primary microcephaly (PM) b...Primary hereditary microcephaly (MCPH) comprises a group of genetically heterogeneous disorders characterized by severe microcephaly and mild intellectual disability. It differs from syndromic primary microcephaly (PM) by the lack of syndromic features and major brain malformations. We evaluated the genetic diagnostic yield, pathogenic mechanisms, and clinical features of these two PM groups in 87 patients from 64 families. Exome sequencing was performed on probands, 52 of whom had consanguineous parents. The diagnostic yield was 53.1%. Of the 34 disease-causing variants identified, 15 were novel, with 83.7% being biallelic. MCPH-associated genes were found in 17.2% of families, while syndromic PM accounted for 35.9%. Most patients in both groups had speech delay. In the MCPH group, borderline to mild intellectual disability, independent of microcephaly severity, and behavioral abnormalities were prominent, whereas severe intellectual disability was more common in the syndromic group. Notably, most genes associated with MCPH are involved in mitotic division and DNA repair pathways, while those in syndromic PM are involved in transcription regulation and cell trafficking pathways. A bird-like facial gestalt was observed in patients from both groups with genes related to mitotic division and DNA repair. In addition, we expanded the genetic heterogeneity to include a potential candidate gene, KNTC1.
Spinal muscular atrophy (SMA), linked to chromosome 5q, is a rare hereditary neurodegenerative disease characterized by progressive motor neuron loss. It is classified into subtypes based on age at onset and the highest...Spinal muscular atrophy (SMA), linked to chromosome 5q, is a rare hereditary neurodegenerative disease characterized by progressive motor neuron loss. It is classified into subtypes based on age at onset and the highest motor milestone achieved. This cross-sectional observational study aimed to describe the clinical profile of patients with types 2 and 3 SMA followed within the Brazilian Public Health System (SUS). Clinical data from patients with types 2 and 3 SMA followed at nine national reference centers (2020-2021) were analyzed. A total of 155 patients were included: 76 with type 2 and 79 with type 3 SMA. Disease duration was longer in type 3 patients. Time from symptom onset to genetic confirmation was also longer in this group. Functional impairment was observed in both subtypes. Type 2 patients had lower HFMSE scores overall, though higher scores were seen among those on disease-modifying therapies. In type 3, earlier symptom onset and longer disease duration were associated with worse motor outcomes. HFMSE scores varied with treatment use and disease duration. Findings reveal the clinical heterogeneity of SMA and emphasize the impact of diagnostic delays and disease duration on function. Early diagnosis and ongoing multidisciplinary care are crucial.
Genetic myopathies encompass a heterogeneous spectrum of neuromuscular disorders whose diagnosis remains challenging despite major technological advances. Traditional methods such as clinical evaluation, creatine kinase...Genetic myopathies encompass a heterogeneous spectrum of neuromuscular disorders whose diagnosis remains challenging despite major technological advances. Traditional methods such as clinical evaluation, creatine kinase measurement, electromyography, and muscle histopathology remain valuable tools for recognizing disease patterns and, when clinically indicated, for complementing and guiding molecular investigations. However, genetically complex or atypical cases still lack an appropriate approach for assertive diagnosis. Aiming to shed light on emerging integrative molecular approaches, this review will discuss the evolving diagnostic landscape of myopathies, highlighting the integration of next-generation molecular tools with conventional methodologies for assertive diagnosis. Long-read sequencing and optical genome mapping have markedly increased diagnostic yield by enabling comprehensive detection of structural variants and complex genomic rearrangements in different myopathies. Complementary proteomic and transcriptomic analyses provide functional insight into how genetic variants alter protein expression and cellular pathways, supporting biomarker discovery and therapeutic development. Together, these omics approaches bridge the gap between genetic alterations and their functional and clinical manifestations in myopathies. They improve the interpretation of variants of uncertain significance, facilitate the identification of biomarkers linked with disease severity or therapeutic response, and support the development of personalized therapeutic strategies, advancing precision medicine in neuromuscular disorders.
WNT10A mutations, a major genetic determinant of dental agenesis and ectodermal dysplasia, exert profound effects on craniofacial development. Although classified as rare disorders, these mutations account for more than...WNT10A mutations, a major genetic determinant of dental agenesis and ectodermal dysplasia, exert profound effects on craniofacial development. Although classified as rare disorders, these mutations account for more than half of oligodontia cases, reflecting their critical role. The associated phenotypes span a broad clinical spectrum, ranging from isolated tooth agenesis to complex multisystem disorders, including hypodontia, enamel and root defects, palmoplantar keratoderma, alopecia, nail dystrophy, skin xerosis, hypohidrosis, eyelid cysts, and skin cancer, skeletal abnormalities and impaired bone homeostasis, underscoring their systemic impact. This review synthesizes current biological and clinical knowledge by linking phenotypes of WNT10A mutations to disruptions in Wnt/β-catenin signaling and its interactions with BMP, SMAD, RANK/RANKL/OPG, VEGF, and other regulatory pathways. Altered pathway activity affects key processes in tooth morphogenesis, osteogenesis, cellular proliferation, and tissue maintenance, offering mechanistic explanations for the heterogeneity and severity of patient presentations. A clearer understanding of these pathways is essential for improving diagnosis and management of WNT10A-associated oligodontia, particularly in treatment planning for growth-dependent interventions, regenerative strategies, and implant rehabilitation. Despite significant progress, critical gaps remain in defining the molecular basis of variable expressivity and genotype-phenotype relationships. Elucidating these mechanisms will be pivotal for advancing precision approaches in dental and craniofacial care.
CTLA-4 haploinsufficiency is caused by heterozygous variants in CTLA4. We report a cohort of five patients with a clinical presentation including immune dysregulation, hypogammaglobulinemia, lung damage, and gastrointest...CTLA-4 haploinsufficiency is caused by heterozygous variants in CTLA4. We report a cohort of five patients with a clinical presentation including immune dysregulation, hypogammaglobulinemia, lung damage, and gastrointestinal symptoms, consistent with CTLA-4 haploinsufficiency. Patients ranged from 10 to 23 years of age, with three presenting before 7 years. Immunoglobulin levels and lymphocyte subpopulations were evaluated. All the patients evaluated showed low levels of CTLA-4 and lymphoproliferation in unstimulated conditions. Treatment before genetic diagnosis consisted mainly of intravenous immunoglobulin replacement and pharmacological immunosuppression. Heterozygous variants in CTLA4 were detected by exome sequencing. Immunological evaluation revealed reduced CTLA-4 expression and spontaneous lymphoproliferation. The identified heterozygous CTLA4 variants included two novel variants, one previously classified as likely pathogenic, one as pathogenic, and one as a variant of uncertain significance. These findings expand the spectrum of CTLA4 variants and support their clinical relevance.
Hereditary optic neuropathies comprise a genetically heterogeneous group of disorders caused by pathogenic variants in mitochondrial and nuclear genes. Despite increasing diagnostic yields, many patients remain without a...Hereditary optic neuropathies comprise a genetically heterogeneous group of disorders caused by pathogenic variants in mitochondrial and nuclear genes. Despite increasing diagnostic yields, many patients remain without a molecular diagnosis. We report a novel candidate heterozygous variant in the PHB1 (Prohibitin 1) gene in a large family affected by autosomal dominant optic atrophy. A three-generation family with slowly progressive visual acuity loss due to optic neuropathy and an apparent autosomal dominant pattern was clinically characterized and recruited for genetic counseling. Exome sequencing and genome-based linkage mapping were performed, alongside protein modeling and in vitro experiments to obtain functional evidence. Family-based whole-genome linkage mapping identified a heterozygous missense variant, c.440C>T (p.Ser147Phe), in PHB1 in all five affected individuals. The variant substitutes p.Ser147Phe within an evolutionarily conserved alpha-helix domain of PHB1, a mitochondrial protein with multiple roles. In silico modeling suggested that p.Ser147Phe may disrupt PHB1 stability and function through loss of hydrogen bonding, steric hindrance, and altered hydrophobic interactions. In vitro experiments suggested potential alterations in mitochondrial dynamics in variant carriers, including a changed ratio of L-OPA1 to S-OPA1 compared with non-carriers. We present initial evidence that PHB1 is a novel candidate gene potentially associated with dominant optic atrophy or a related mitochondrial disorder. This represents the first report implicating PHB1 in a Mendelian disease. Further studies are required to validate this association.
Fertilization failure remains a major cause of infertility and poor outcomes in assisted reproductive technology, yet the underlying genetic mechanisms are incompletely understood. In this study, we investigated two unre...Fertilization failure remains a major cause of infertility and poor outcomes in assisted reproductive technology, yet the underlying genetic mechanisms are incompletely understood. In this study, we investigated two unrelated infertile men presenting with macrozoospermia and recurrent fertilization failure following intracytoplasmic sperm injection (ICSI). Whole-exome sequencing identified biallelic variants in NUP210L, including a homozygous variant (c.3361C>T) in one patient and compound heterozygous variants (c.3853C>G and c.2965G>T) in another, which were confirmed by Sanger sequencing and predicted to be deleterious. Functional analyses revealed markedly reduced NUP210L expression in the patients' spermatozoa. Morphological assessment by Papanicolaou staining and scanning electron microscopy showed enlarged and irregular sperm heads accompanied by multiple flagella, while severely impaired chromatin condensation was observed under transmission electron microscopy. Consistently, immunofluorescence demonstrated significantly decreased expression of the protamines PRM1 and PRM2, indicating disruption of the histone-to-protamine transition during spermatogenesis. Expression analyses further revealed that NUP210L is predominantly expressed in spermatids in both human and mouse testes, supporting its role in late spermatogenic stages. Collectively, these findings provide evidence linking NUP210L deficiency to impaired chromatin condensation and fertilization failure, thereby expanding the genetic spectrum of fertilization failure and offering crucial insights for genetic diagnosis and clinical management in assisted reproduction.
Polyglucosan body myopathy type 2 (PGBM2; OMIM #616199) is an autosomal recessive myopathy caused by biallelic variants in GYG1, which encodes glycogenin-1. It is characterized by progressive muscle weakness and PAS-posi...Polyglucosan body myopathy type 2 (PGBM2; OMIM #616199) is an autosomal recessive myopathy caused by biallelic variants in GYG1, which encodes glycogenin-1. It is characterized by progressive muscle weakness and PAS-positive, diastase-resistant polyglucosan inclusions on muscle biopsy. We report a 64-year-old woman who developed progressive proximal weakness beginning in her early 50s, with polyglucosan bodies identified on muscle histopathology. Genome sequencing (GS) detected a single heterozygous pathogenic splice-site variant, NM_004130.4(GYG1):c.143+3G>C. Given strong histopathologic evidence of PGBM2, GS data were reanalyzed, revealing an additional rare deep intronic variant, NM_004130.4(GYG1):c.7+992T>G, predicted to activate a cryptic exon. RNA sequencing (RNA-seq) confirmed aberrant splicing from both variants, demonstrating exon 2 skipping associated with c.143+3G>C and cryptic exon inclusion caused by c.7+992T>G. Variant phasing posed a diagnostic challenge due to unavailable parental DNA, and long-range PCR results were inconclusive. Long-read GS definitively demonstrated that the two variants were in trans, establishing compound heterozygosity and confirming the molecular diagnosis. These findings enabled reclassification of the deep intronic variant as likely pathogenic. This case highlights the diagnostic limitations of conventional phasing approaches in adult-onset recessive disorders and demonstrates the clinical utility of integrating genome reanalysis, RNA-seq, and long-read GS for resolving complex phasing challenges.
Inborn errors of metabolism (IEM) are frequently underdiagnosed in low-resource settings due to limited diagnostic infrastructure. We hypothesized that an integrated clinical-genomic approach could improve diagnosis and...Inborn errors of metabolism (IEM) are frequently underdiagnosed in low-resource settings due to limited diagnostic infrastructure. We hypothesized that an integrated clinical-genomic approach could improve diagnosis and management of these conditions. Nineteen Pakistani families with clinically suspected IEM underwent systematic clinical assessment, available biochemical testing, and whole-exome sequencing (WES). Variants were classified according to ACMG/AMP guidelines using evidence from population databases, in silico prediction tools, segregation analysis, and genotype-phenotype correlation. Clinical diagnoses and management strategies were reassessed based on molecular findings. WES provided a molecular diagnosis in 90% (17/19) of families and enabled targeted therapeutic interventions in 70% (13/19). However, clinical outcomes were variable due to advanced disease in some cases and limited follow-up. Seven novel variants were identified in CYP27B1, DYM, MTTP, ALDH3A2, USP53, BRAF, and JAG1, while twelve recurrent mutations were detected in PIGN, GCDH, CLCN7, RNASEH2C, ABCB11, MPV17, IDUA, SMPD1, FBP1, SLC37A4, ACADM, and UGT1A1. Integrating genomic findings with clinical reassessment improved diagnostic precision. An integrated clinical-genomic approach enabled accurate diagnosis of pediatric IEM in resource-limited settings, with particular utility in children with metabolic disorders in a consanguineous population. Identification of both novel and recurrent variants expanded the genotypic and phenotypic spectrum of these disorders and highlighted the clinical utility of genomic diagnostics in optimizing patient care.
van Oirsouw ASE, Hsieh TC, Koetsier M
… +28 more, Alali A, Albuainain F, Bacchelli E, Barakat TS, Capri Y, Chantot-Bastaraud S, Capra V, Carere DA, Clement E, Elkhateeb N, Franchi M, Li JM, Matthews N, McNiven V, Mehta SG, Nakamura M, Phornphutkul C, Revencu N, Scala M, Shallow N, Stefanich J, Viggiano M, Visconti P, Walker S, Zara F, Alders M, Koeleman BPC, Oegema R
The recently delineated KDM2B-associated neurodevelopmental disorder (NDD) is characterized by developmental delay and variable co-morbidity. Genotype-phenotype correlations are emerging, in particular a distinct clinica...The recently delineated KDM2B-associated neurodevelopmental disorder (NDD) is characterized by developmental delay and variable co-morbidity. Genotype-phenotype correlations are emerging, in particular a distinct clinical presentation caused by CxxC domain variants. We report here a novel intragenic deletion which leads to in vitro expression of a shortened KDM2B protein lacking the complete CxxC domain. In addition, we present data on 12 other individuals; two with larger 12q24.31 microdeletions, one with a frameshift variant, and nine with missense variants. We analyzed genotype-phenotype correlations of this cohort combined with previously reported individuals (n = 68) and classify 37 variants in 47 individuals as pathogenic or likely pathogenic. We observe a highly penetrant CxxC-related phenotype with distinct facial features supported by GestaltMatcher. In contrast, our findings point to variable expressivity and incomplete penetrance of loss-of-function variants and JmjC domain variants complicating variant classification and genetic counseling. We identify KDM2B as a strong contributor to the 12q24.31 microdeletion syndrome, while also addressing the role of additional genes in the region. Thus, our study defines the KDM2B-NDD's clinical spectrum and highlights the importance of integrating molecular, (epi)genetic, and phenotypic data in NDD diagnostics.
FUZ, a component of the CPLANE (ciliogenesis and planar polarity effector) complex, regulates primary ciliogenesis. Five patients of various types of skeletal dysplasia with biallelic FUZ variants have been reported to d...FUZ, a component of the CPLANE (ciliogenesis and planar polarity effector) complex, regulates primary ciliogenesis. Five patients of various types of skeletal dysplasia with biallelic FUZ variants have been reported to date, yet the gene-disease relationship has not been established. Here, we report a patient with ciliopathy with a novel homozygous missense variant in FUZ. This patient shares phenotypes with all the previously reported patients and presents with novel phenotypes: aorto-pulmonary window (AP window) and Hirschsprung disease. These phenotypes can be explained by the inhibition of neural crest cell migration due to abnormal Sonic hedgehog (Shh) signaling caused by primary cilia dysfunction. In silico three-dimensional structural analysis predicted that the variant alters interactions between FUZ and CPLANE2 (RSG1), potentially disrupting ciliogenesis. This report provides additional evidence for FUZ as a causative gene for ciliopathy, offering novel insights into the phenotype spectrum and molecular mechanisms of FUZ-related ciliopathy.
This study aims to characterize the clinical phenotypes of children with SYNGAP1-related neurodevelopmental disorders (SRDs), explore the genotype-phenotype correlation, and guide optimal clinical management. Clinical da...This study aims to characterize the clinical phenotypes of children with SYNGAP1-related neurodevelopmental disorders (SRDs), explore the genotype-phenotype correlation, and guide optimal clinical management. Clinical data of 99 Chinese children with SRDs were retrospectively collected, including genetic results, clinical features, electroencephalogram (EEG), cranial imaging, and treatment responses. The correlation between clinical phenotype and genotype was analyzed using Pearson correlation and logistic regression analyses. All children with SRDs exhibited varying degrees of developmental delay, with severe developmental delay being predominant (82/99, 82.8%). The comorbidity rate of autism spectrum disorder (ASD) was high (60/99, 60.6%), and muscle tone abnormalities (21/99, 21.2%), as well as sleep and feeding problems, were also common. Epilepsy occurred in 68.7% of patients, with a mean onset age of 2.14 ± 0.99 years. The most common seizure type was eyelid myoclonia (37/68, 54.4%), and approximately one-third of the children developed drug-resistant epilepsy (DRE). For most phenotypes, no significant differences were observed between truncating and missense mutations. However, domain analysis indicated a significantly higher proportion of myoclonic seizures in the PH domain (9/14, 64.3%), an extremely high epilepsy incidence in the C2 domain (92.3%), and the lowest incidence of DRE in the SH3 domain (2/13, 15.4%), suggesting mutations in different functional regions may have specific clinical impacts. Antiseizure medication (ASM) treatment was generally effective, with 39.7% of children achieving seizure freedom. Eyelid myoclonia was identified as an independent risk factor for poor ASM response and DRE. The severity of developmental delay was negatively correlated with epilepsy onset age. Significant EEG abnormalities and ASD comorbidity were significant risk factors for severe developmental delay. In conclusion, SRDs exhibit a clinical profile centered on severe developmental delay, high epilepsy incidence, and ASD comorbidity. Partial domain-specific genotype-phenotype associations exist. Eyelid myoclonia is an important negative prognostic indicator for epilepsy. This study provides clinical evidence based on a Chinese population for the early diagnosis, prognosis assessment, and individualized treatment of SRDs.
SLC20A1 encodes the ubiquitously expressed phosphate transporter PiT1, a protein with roles extending beyond phosphate homeostasis to include regulation of proliferation, differentiation, apoptosis, and embryonic develop...SLC20A1 encodes the ubiquitously expressed phosphate transporter PiT1, a protein with roles extending beyond phosphate homeostasis to include regulation of proliferation, differentiation, apoptosis, and embryonic development. While heterozygous SLC20A1 variants have been associated with urinary tract malformations, the impact of biallelic loss-of-function was unknown. We report the first human case of a biallelic homozygous predicted loss of function variant in SLC20A1 (c.674_675delAA; p.K225TfsX34) in a child with multiple congenital anomalies including tetralogy of Fallot, unilateral renal agenesis, postaxial polydactyly, growth impairment, and developmental delay. PiT1 expression was decreased in fibroblasts of the proband. Transcriptome analysis of patient-derived fibroblasts suggests significant dysregulation of pathways critical for organogenesis, including PI3K-Akt, Wnt, MAPK, and BMP signaling. Population screening identified a carrier frequency of 1:432 among Ashkenazi Jewish individuals. Our findings expand the phenotypic spectrum of SLC20A1-related disease and provide evidence that biallelic PiT1 deficiency causes a previously unrecognized multisystem developmental disorder.
Biallelic loss-of-function variants in FBXO31 cause autosomal-recessive intellectual disability. A recurrent de novo variant, c.1000G>A(p.Asp334Asn), has been described in association with an autosomal-dominant phenotype...Biallelic loss-of-function variants in FBXO31 cause autosomal-recessive intellectual disability. A recurrent de novo variant, c.1000G>A(p.Asp334Asn), has been described in association with an autosomal-dominant phenotype. To refine this phenotype and its clinical implications, we re-evaluated three published cases and ascertained four additional probands via advocacy networks, GeneMatcher, and clinician referral. Phenotyping included neurologic, behavioral, and dysmorphology assessment. All seven individuals carried the recurrent de novo FBXO31 p.Asp334Asn variant. A core neurodevelopmental profile was observed and included cerebral palsy (mixed hypotonia, spasticity, and dystonia), global developmental delay/intellectual disability, and speech impairment. Neuropsychiatric features were sometimes prominent and included attention-deficit/hyperactivity disorder, anxiety, stereotypies, autistic features, and behavioral dysregulation. Neuroimaging often showed a hypoplastic corpus callosum and posterior-predominant white-matter changes. In one individual, gray matter heterotopias were also observed. A subtle but consistent facial gestalt was noted. Recurrent FBXO31 p.Asp334Asn variants lead to a recognizable neurodevelopmental syndrome. Based on our findings, we recommend including FBXO31 in diagnostic algorithms for cerebral palsy and neurodevelopmental disorders. We propose the descriptive term "autosomal dominant FBXO31-associated neurodevelopmental disorder," and-consistent with the validating laboratory and with support from the FBXO31 Foundation-propose the eponym "Kruer syndrome."
The LYSET gene encodes the LYSET transmembrane protein, which regulates lysosome biogenesis by activating the mannose-6-phosphate (M6P) pathway. This is an autosomal recessive, ultrarare, and severe progressive skeletal...The LYSET gene encodes the LYSET transmembrane protein, which regulates lysosome biogenesis by activating the mannose-6-phosphate (M6P) pathway. This is an autosomal recessive, ultrarare, and severe progressive skeletal dysplasia with coarse facies, distended abdomen, short stature, and severe physical disability. In a diagnostic odyssey, we report a female patient, born in 2008, daughter of consanguineous parents, with hand contractures and a typical facial appearance since 5 months old. She was clinically diagnosed at 2 years old with contractures and severe dysplasia. Systolic murmur, thickening of mitral and aortic valves, and tricuspid regurgitation were observed. Nine enzymes showed increased levels in plasma, and seven showed decreased levels in fibroblasts. Abnormal sialic acid profile and GAGs (glycosaminoglycans) were detected in urine. No variants were identified during more than a decade of investigation. A whole-genome analysis identified the homozygous nonsense variant NM_001098621.4:c.112C>T (p.Gln38Ter) in the LYSET gene. The patient had not been diagnosed before due to the recent association of the gene with the lysosomal hydrolase labeling pathway. She died in 2018 from respiratory causes. The discovery of the relationship between the LYSET gene and lysosomal biogenesis was determinative of the diagnostic conclusion. Cases of dysostosis multiplex can be highly challenging due to the rarity of the disease and its clinical similarity to mucopolysaccharidosis (MPS) and mucolipidosis II/III (MLII/III). This is the first western report of a challenging case of an extensive diagnostic odyssey and demonstrates that the LYSET gene must be considered in the differential diagnosis when M6P-labeled lysosomal enzymes are altered.