Homozygous Variant Research Articles

Clinical follow-up of 2 families with glomerulopathy caused by COQ8B gene variants and literature review

BackgroundPrimary coenzyme Q10 (CoQ10) deficiency is an autosomal recessive genetic disease caused by mitochondrial dysfunction. Variants in Coenzyme Q8B (COQ8B) can cause primary CoQ10 deficiency. COQ8B-related glomerulopathy is a recently recognized glomerular disease that most often presents as steroid-resistant nephrotic syndrome (SRNS) in childhood. The disease often progresses to kidney failure and the renal histopathology is most commonly focal segmental glomerulosclerosis (FSGS).MethodsFour SRNS cases (2 females and 2 males) from 2 unrelated families who were followed clinically for nearly 3 years. Clinical exome testing and analyses were performed by MyGenostics Laboratory in China to evaluate unexplained proteinuria given the strong family history of glomerular disease and histologic evidence of SRNS. Pathogenic variants were identified in COQ8B in the exome studies and confirmed by direct sequencing.ResultsClinical exome sequencing revealed biallelic variants of the COQ8B gene in 2 families. In the Family 1, the oldest of three affected siblings died of renal failure at 11 years of age. Based on the results of genetic testing which identified a homozygous variant of COQ8B, the other two affected siblings with mild proteinuria and normal renal function were treated with CoQ10 oral supplementation at an early stage. Coenzyme Q10 treatment was effective in reducing proteinuria levels in both patients from Family 1 over the first 6 months and the two patients still have low-level proteinuria and normal renal function at nearly three years. In Family 2, clinical exome sequencing revealed a compoundheterozygous variants of COQ8B in a patient with biopsy- proven FSGS. His disease was unresponsive to prior treatment with glucocorticoids and cyclosporine. Oral CoQ10 was initiated based on his genetic diagnosis and was it was effective in reducing proteinuria over the first 5 months months of therapy. However after 1 year, his disease progressed tokidney failure. Kidney transplantation was performed at 5 years of age and his condition has been stable without rejection and no recurrence of disease.ConclusionsCOQ8B gene variant-related glomerulopathy often presents as SRNS without obvious extrarenal manifestations. The histopathology is mainly FSGS and follows an autosomal recessive mode of inheritance. Some patients may benefit from early coenzyme Q10 supplementation. For patients whose disease progresses to kidney failure, kidney transplantation can be an effective treatment. For children with unexplained proteinuria and abnormal renal function, genetic testing should be performed early in the course of disease to guide therapy where possible and improve prognosis.

IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta.

Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In addition to peripheral neuropathy, immunodeficiency and tooth abnormalities are occasionally present. Here, we report the identification of a homozygous nonsense variant in the ITPR3 gene in Lancashire Heeler dogs, presenting with a severe developmental enamel defect and reduced nerve conduction velocity. We studied the primary skin fibroblasts of the affected dogs and observed that the nonsense variant in ITPR3 led to a complete absence of full-length IP3R3 protein. Unexpectedly, the protein levels of IP3R1 and IP3R2 were also markedly decreased, suggesting co-regulation. Functional Ca2+ measurements revealed reduced IP3R-mediated Ca2+ flux upon stimulation of G-protein-coupled-receptors in the affected dog fibroblasts. These findings highlight the first spontaneous mammalian phenotype caused by a nonsense variant in ITPR3, leading to the loss of IP3R3. The human and canine IP3R3 proteins are highly similar, and our study suggests that the tissue involvement resulting from the receptor's dysfunction is also conserved. In summary, IP3R3 is critical for enamel formation and peripheral nerve maintenance.

Genetic analysis of a child with Leukoencephalopathy with ataxia caused by a homozygous variant of CLCN2 gene and a literature review

To explore the clinical manifestations and genetic characteristics of a child with Leukoencephalopathy with ataxia (LKPAT) caused by a CLCN2 gene variant. A retrospective analysis was conducted on the clinical data of a child admitted to Hunan Children's Hospital in June 2024 due to "intermittent convulsions for 13 days". Peripheral blood samples were collected from the child and his parents for whole exome sequencing, followed by Sanger sequencing validation and pathogenicity analysis of candidate variants. Literature searches were performed using the keywords "CLCN2 gene" "chloride channel-2" "leukoencephalopathy with ataxia/LKPAT" "leukoencephalopathy" in both Chinese and English on CNKI, Wanfang, and PubMed databases. The search time was set from the establishment of the databases to July 31, 2024. Childhood-onset LKPAT literature was screened and analyzed. This study was approved by the Medical Ethics Committee of Hunan Children's Hospital (Ethics No. HCHLL-2024-351). The child was a 7-month-and-26-day-old male infant born to consanguineous parents, presenting with epileptic seizures and borderline development. Cranial MRI revealed symmetrical long T2 signal shadows in the posterior limb of the internal capsule, cerebral peduncle, pons, and middle peduncle of the cerebellum. Video electroencephalogram (EEG) showed an abnormal childhood EEG with one focal seizure. Whole exome sequencing revealed a homozygous c.2201dup (p.Glu735Ter) variant in the CLCN2 gene of the child. Sanger sequencing confirmed that the variant was inherited from both parents. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), this variant was classified as pathogenic (PVS1+PM3_Supporting+PM2_Supporting). A total of 8 relevant literature were retrieved, together with the present case, 16 childhood-onset LKPAT patients were cumulatively reported, which consisted of 9 males and 7 females. Twelve CLCN2 gene variants were involved, including 2 nonsense variants, 3 missense variants, 7 frameshifting variants, 2 c.61dup variants, and 5 c.1709G>A variants. The initial symptoms of the 16 patients included headache, ataxia, epileptic seizures, spasticity, developmental delay, lower back pain, hearing impairment, and intention tremor. Three patients had onset of the disease before the age of one, of which 2 had epileptic seizures as the initial symptom. The homozygous variant CLCN2: c.2201dup (p.Glu735Ter) is considered the pathogenic cause of LKPAT in this child, marking the first childhood-onset case reported in China. Genetic testing has facilitated the diagnosis of childhood-onset LKPAT and expanded the spectrum of CLCN2 gene mutations.

Bone marrow transplantation reverses metabolic alterations in multiple sulfatase deficiency: a case series

BackgroundMultiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD. Other than symptomatic treatment, no curative therapy exists as of yet for MSD. Eight out of these 17 sulfatases are primarily localized in the lysosome.MethodsTwo siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from the donor cells.ResultsThere is evidence of correction of currently available biomarkers within 3 months post-HCT. Untargeted metabolomics also shows continued correction of multiple biochemical abnormalities in the post-HCT period. Furthermore, this article also presents the neuropsychological outcomes of these children as well as the results of untargeted metabolomics analysis in this condition.ConclusionsThese data suggest biochemical benefits post-transplant along with slowing of disease progression. Long-term follow-up is necessary to fully evaluate the therapeutic benefit of HCT in MSD.

A recurrent loss-of-function variant in DRC1 causes non-syndromic severe asthenozoospermia with favorable intracytoplasmic sperm injection and pregnancy outcomes.

Asthenozoospermia, characterized by reduced sperm motility, is a common cause of male infertility. Multiple morphological abnormalities of the sperm flagella (MMAF) represent a severe and genetically heterogeneous form of asthenozoospermia. Over 50 genes have been associated, but approximately half of MMAF cases remain unexplained. DRC1, a gene involved in the nexin-dynein regulatory complex (N-DRC), has been linked to MMAF and primary ciliary dyskinesia (PCD), often with significant variability in clinical presentation. His study aimed to identify novel pathogenic DRC1 variants in MMAF patients, assess their impact on sperm flagellar structure, and evaluate intracytoplasmic sperm injection (ICSI) and pregnancy outcomes. A cohort of 196 non-syndromic MMAF patients was analyzed using whole exome sequencing (WES). Functional validation of candidate variants included immunofluorescence to assess protein expression and transmission electron microscopy (TEM) to identify ultrastructural abnormalities. Assisted reproductive therapy outcomes were also evaluated. WES identified a recurrent homozygous frameshift variant in DRC1 NM_145038.5: c.109dup; p.(Gln37ProfsTer30) in four patients (2%), all of North African origin, none of whom suffer from PCD-related symptoms. The variant caused a complete absence of DRC1 protein in spermatozoa. TEM showed flagellar abnormalities, with 10% of axonemal sections revealing peripheral doublet dissociation, suggesting N-DRC instability. ICSI resulted in a 68.5% fertilization rate, with three out of four couples successfully delivering healthy children. The identification of a novel and recurrent pathogenic DRC1 variant broadens the mutation spectrum associated with MMAF. The absence of systemic PCD symptoms suggests that DRC1 deficiency may primarily affect spermatogenesis. Notably, the phenotypic spectrum might be influenced by the genetic background, varying across populations. Favorable ICSI outcomes, with a 68.5% fertilization rate and successful pregnancies in three out of four couples, highlight the effectiveness of assisted reproductive techniques for patients with this genetic defect.

An ADPRS variant disrupts ARH3 stability and subcellular localization in children with neurodegeneration and respiratory failure

ADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of ADP-ribosylation is implicated in neurodegenerative diseases. In this study, genetic testing via exome sequencing was used to identify the underlying disease in two siblings with developmental delay, seizures, progressive muscle weakness, and respiratory failure following an episodic course. This identified a novel homozygous variant in the ADPRS gene (c.545A>G, p.His182Arg) encoding the mono(ADP-ribosyl) hydrolase ARH3, confirming the diagnosis of childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS) in these two children. Mechanistically, the ARH3H182R variant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and, subsequently, reduced protein expression. The ARH3H182R mutant additionally fails to localize to the nucleus, which further resulted in accumulated mono-ADP ribosylated species in cells. The children's clinical course combined with the biochemical characterization of their genetic variant develops our understanding of the pathogenic mechanisms driving CONDSIAS and highlights a critical role for ARH3-regulated ADP-ribosylation in nervous system integrity.

Biallelic variants in SREBF2 cause autosomal recessive spastic paraplegia.

Hereditary spastic paraplegias (HSPs) refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons. To date, a significant number of patients still have not received a definite genetic diagnosis. Therefore, identifying unreported causative genes continues to be of great importance. Here, we perform whole exome sequencing in a cohort of Chinese HSP patients. Three homozygous variants (p.L604W, p.S517F, and p.T984A) within the sterol regulatory element-binding factor 2 (SREBF2) gene are identified in one autosomal recessive family and two sporadic patients, respectively. Co-segregation is confirmed by Sanger sequencing in all available members. The three variants are rare in the public or in-house database and are predicted to be damaging. The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila. We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2, eventually impairing the autophagosomal and lysosomal functions. The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila. Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.

Severe neonatal hypotonia due to SLC30A5 variant affecting function of ZnT5 zinc transporter.

The tightly-regulated spatial and temporal distribution of zinc ion concentrations within cellular compartments is controlled by two groups of Zn2+ transporters: the 14-member ZIP/SLC39 family, facilitating Zn2+ influx into the cytoplasm from the extracellular space or intracellular organelles; and the 10-member ZnT/SLC30 family, mobilizing Zn2+ in the opposite direction. Genetic aberrations in most zinc transporters cause human syndromes. Notably, previous studies demonstrated osteopenia and male-specific cardiac death in mice lacking the ZnT5/SLC30A5 zinc transporter, and suggested association of two homozygous frameshift SLC30A5 variants with perinatal mortality in humans, due to hydrops fetalis and hypertrophic cardiomyopathy. We set out to decipher the molecular basis of a severe hypotonia syndrome. Combining homozygosity mapping and exome sequencing studies of consanguineous Bedouin kindred, as well as transfection experiments and zinc monitoring in HEK293 cells, we demonstrate that a bi-allelic in-frame 3bp deletion variant in SLC30A5, deleting isoleucine within the highly conserved cation efflux domain of the encoded ZnT5, results in lower cytosolic zinc concentrations, causing a syndrome of severe non-progressive neonatal axial and limb hypotonia with high-arched palate and respiratory failure. There was no evidence of hydrops fetalis, cardiomyopathy or multi-organ involvement. Affected infants required nasogastric tube or gastrostomy feeding, suffered from various degrees of respiratory compromise and failure to thrive and died in infancy. Thus, a biallelic variant in SLC30A5 (ZnT5), affecting cytosolic zinc concentrations, causes a severe hypotonia syndrome with respiratory insufficiency and failure to thrive, lethal by 1 year of age.

A novel homozygous variant in exon 4 of the GALNT3 gene causing hyperphosphataemic familial tumoural calcinosis in a family from China

A novel homozygous variant in exon 4 of the GALNT3 gene causing hyperphosphataemic familial tumoural calcinosis in a family from China

Whole genome sequencing reveals candidate causal genetic variants for spastic syndrome in Holstein cattle

Bovine spastic syndrome (SS) is a progressive, adult-onset neuromuscular disorder (NMD). SS is inherited but the mode of inheritance is unclear. The aim of this study was to characterize the phenotype and to identify a possible genetic cause of SS by whole-genome sequencing (WGS) and focusing on protein-changing variants. Seven affected unrelated Holstein cattle of both sexes were referred for SS at a mean age of 5.3 years (S.D.±1.1) showing intermittent spasm of the skeletal muscles of the pelvic girdle. Assuming monogenic recessive inheritance, analysis of the WGS data did not reveal any private variants common to all cases. Searching for homozygous rare variants considering each case individually, allowed the identification of a rare recessive likely pathogenic missense variant in TOR3A for one case with an allele frequency of 1.69% in a global Holstein population. In the remaining six SS cases, we identified seven potentially dominant de novo mutations or inherited alleles as private heterozygous, mostly missense, variants of uncertain significance involving seven different NMD candidate genes: MPEG1, LHX8, WHAMM, NGRN, TTN, ATP1A1, PCDH1. All eight candidate causal variants identified were predicted to be deleterious. This study describes for the first time WGS findings in confirmed cases of bovine SS and provides evidence for a heterogeneous genetic cause of SS in cattle.

Variant Spectrum of Renal Ciliopathies in Turkish Cohort and Genotype-Phenotype Association Specifically in Autosomal Dominant Polycystic Kidney Disease.

Renal ciliopathies are a genetically and phenotypically heterogeneous group of diseases characterized by cystic and dysplastic kidneys. The aim of this study was to investigate the correlation between genetic changes that cause renal ciliopathies and phenotypic outcomes. The study group consisted of 137 patients diagnosed with renal ciliopathy disease. One hundred nineteen patients had ADPKD phenotype, 7 patients had ARPKD phenotype, 4 patients had nephronophthisis, 1 patient had Senior-Loken syndrome, 4 patients had Bardet-Biedl syndrome, 1 patient had Joubert syndrome and 1 patient had Meckel Gruber syndrome phenotype. Among patients with autosomal dominant polycystic kidney disease, patients with the PKD1 gene mutation had higher creatinine levels (p value: 0.020) and no arachnoid cysts were revealed in the PKD2 group (p value: 0.014). When the domains were compared, the finding of arachnoid cyst in patients with mutations in the transmembrane domain was statistically significant (p value: 0.021). Homozygous likely pathogenic variant in the TCTN1 gene was reported in a fetus who had findings of Meckel-Gruber syndrome; microphthalmia and cardiac hypoplasia were reported as novel findings. As a conclusion, we identified variant spectrum of renal ciliopathies in Turkish cohort and revealed the association between the transmembrane domain and arachnoid cyst.

A Rare Cause of Neonatal Salt Wasting Syndrome: Clinical Management of a Case Diagnosed with Pseudohypoaldosteronism Due to a Novel Homozygous Variant in the SCNN1B Gene.

Pseudohypoaldosteronism (PHA) is a rare disorder that, if not promptly recognized and treated, can lead to life-threatening hyperkalemia resulting in cardiac arrest and death. Systemic PHA is caused by variants that deactivate the epithelial sodium channel (ENaC) subunits. Management is challenging due to high-dose oral replacement therapy, and patients with systemic PHA require lifelong treatment. Here, we present the clinical course of a newborn diagnosed with PHA at 7 days of age due to severe dehydration, inadequate feeding, vomiting, and lethargy. The patient was found to be homozygous for the variant c.1234dup (p.Glu412Glyfs*39) in exon 8 of the SCNN1B gene. The patient had multiple hospitalizations during follow-up and died at the age of 10 months due to pneumonia. Maintaining a high clinical suspicion for PHA is crucial for initiating treatment and preventing potential cardiac arrest and death in these patients. Further research is needed to determine the significance of such novel mutations in this disease.

Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity.

Phosphoribosylaminoimidazole carboxylase (PAICS) deficiency, caused by biallelic variants in PAICS gene, is an inborn error of de novo purine synthesis. Only two patients from a consanguineous family have been reported, with multiple congenital malformations, resulting in early neonatal death. Molecular analysis identified a homozygous p.(Lys53Arg) missense variant. We report the third case of PAICS deficiency in a 7 years old boy, presenting with polymalformative syndrome, but normal neurodevelopment. We report malformations not previously described in PAICS deficiency, notably congenital cardiopathy, and support the consistency of skeletal and oesophageal defects. Genome Sequencing identified the homozygous pathogenic variant p.(Lys53Arg), suggesting a recurrent variant in PAICS. A probable recurrence of PAICS deficiency occurred in a sibling, with a similar polymalformative syndrome antenatally diagnosed, but could not be confirmed molecularly. We further delineate the phenotype of PAICS deficiency and provide new insights concerning prognosis, notably in terms of neurodevelopment.

Hereditary Spastic Paraplegia Linked to Abnormal Splicing From an AIMP1 Missense Variant.

Hereditary spastic paraplegias (HSP) are a diverse group of neurodegenerative diseases characterized by lower limb spasticity and weakness. To date, over 80 genes have been associated with HSP, but many families remain without a molecular diagnosis. In this study, linkage analysis and whole-exome sequencing (WES) were performed to identify the causal gene in a HSP family with autosomal recessive inheritance. Multipoint linkage analysis revealed a maximum significant multipoint LOD score of 4.6 on chromosome 4. WES analysis focused on this region led to the identification of a homozygous missense variant in AIMP1 (c.223G>A). Minigene assays showed that the presumed missense variant in AIMP1 caused loss of the exon 3 donor splice site. Ultimately, this led to the use of an alternative splice site within the intron and the insertion of a premature stop codon. The identification of a novel AIMP1 causal variant contributes to the growing list of HSP genes. Furthermore, it shows that, considering also previous reported cases, disruption of AIMP1 causes a spectrum of disorders ranging from intellectual disability to more complex neurodegenerative diseases.

A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1

A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1

Permanent Neonatal Diabetes with High Insulin Requirements Due to a New Variant in the INS Gene.

Neonatal diabetes is an infrequent disorder that may present as transient, permanent, or syndromic. It is most commonly caused by pathogenic variants involving the ABCC8, KCNJ11, and INS genes. To describe a neonate with permanent diabetes mellitus due to a previously unreported variant in the INS gene, outlining the diagnostic complexities, therapeutic interventions, and related clinical challenges. Neonate with symmetrical intrauterine growth restriction, who presented severe hyperglycemia not associated with ketosis or infectious. He had high insulin requirements and did not respond to sulfonylurea management. Anti-insulin and anti-islet pancreatic antibodies were negative. Genetic sequencing revealed a homozygous missense variant (c.3G>A, p.Met1Ile) in the INS gene, which had not been previously reported in the literature. Timely molecular diagnosis of neonatal diabetes enables optimization of management strategies, mitigating the long-term impact on growth, neurodevelopment, and the occurrence of hypoglycemic episodes.

Loss-of-function of DDR1 is responsible for a chondrodysplasia with multiple dislocations.

Chondrodysplasias with multiple dislocations are rare skeletal disorders characterized by hyperlaxity, joint dislocations, and growth retardation. Chondrodysplasias with multiple dislocations have been linked to pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis. In this study, by exome sequencing analysis, we identified a homozygous nonsense variant (NM_001297654.2: c.1825C > T, p.Arg609*) in the discoidin domain receptor 1 (DDR1) gene in a patient presenting joint dislocations, hyperlaxity, and cerebellar hypoplasia. Functional studies revealed decreased proteoglycan production in patient fibroblasts. We further demonstrated that DDR1 inhibition impaired the Indian Hedgehog (IHH) signaling pathway in chondrocytes, decreased differentiation and mineralization in osteoblasts, and disrupted p38 MAPK signaling in both cell types. Additionally, we showed that DDR1 inhibition affected the non-canonical WNT signaling pathway in human skeletal cells and decreased proteoglycan production in chondrocytes. These findings suggest that DDR1 is a new gene involved in the group of chondrodysplasias with multiple dislocations and highlights its essential role in human skeletal and brain development.

Case report: Clinical and genetic characterization of a novel ALDH7A1 variant causing pyridoxine-dependent epilepsy, developmental delay, and intellectual disability in two siblings

BackgroundPathogenic variants in ALDH7A1 are associated with pyridoxine-dependent epilepsy (PDE), a rare autosomal recessive disorder characterized by epileptic seizures, unresponsiveness to standard antiseizure medications (ASM), and a response only to pyridoxine. Here, we report two patients (from a consanguineous family) with neonatal seizures and developmental delay.Case presentationPatient 1 (a 13-year-old girl) was born normally at term. Her pregnancy was complicated by antiphospholipid syndrome, and persistent vomiting was managed with several medications, including pyridoxine (40 mg daily). Seizures occurred 6 h after birth and did not respond to antiseizure medications. However, they ceased 2 days later when pyridoxine (40 mg daily) was administered. She continued her medications and had delayed early milestones. Phenobarbitone was discontinued at 18 months, and pyridoxine was increased to 100 mg daily at 8 years of age. She was able to join a regular school and performed well. Patient 2, a 12-year-old boy, was delivered normally at term. Seizures started 10 h after birth, and he immediately received 40 mg of pyridoxine. Seizures have been controlled since then, and he experienced delayed milestones. Pyridoxine was increased to 100 mg daily at 7 years of age. He is currently in fifth grade and has dyslexia. Whole exome sequencing (WES) revealed that both patients 1 and 2 harbor a novel homozygous missense variant in ALDH7A1 (NM_001202404: exon 12: c.1168G>C; (p.Gly390Arg)).ConclusionThe present study reports a novel ALDH7A1 variant causing PDE and highlights the associated developmental delay and intellectual disability, despite early seizure control treatment.

Identification of a Founder GLDN Variant Associated With "Lethal" Arthrogryposis in Nunavik Inuit: Implications for Obstetrical and Long-Term Survivors' Management.

Biallelic variants in GLDN have recently been associated with lethal congenital contracture syndrome 11 (LCCS11), a form of fetal akinesia deformation sequence (FADS) with high neonatal mortality. In this report, we describe five individuals from two Canadian Inuit families originating from different communities in Nunavik all affected with FADS and harboring a rare homozygous missense variant, [NM_181789.4:c.82G >C p.(Ala28Pro)] in GLDN. Two pregnancies presented with significant obstetrical complications including placental abruption and hemorrhage. Four infants died shortly after birth, while one survived past the neonatal period. This individual, while apparently asymptomatic during infancy, then presented with progressive neuromuscular and respiratory compromise that became more evident in adolescence. Data from a Nunavik Inuit cohort demonstrated a minor allele frequency (MAF) of 0.03571 for this variant compared to 0.00001341 in the general population, suggesting a founder effect in the Nunavik Inuit population. Our findings support the presence of a founder variant associated with LCCS11 in Nunavik Inuit populations. Our data corroborate those of other reports, demonstrating that LCCS11 is not universally lethal, but long-term survivors are at risk of progressive neuromuscular compromise. We also highlight in this report the significant obstetrical complications associated with this fetal-onset condition.

The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non-kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient.

ATX-FGF/SCA27A has been exclusively associated with heterozygous variants in the FGF14 gene, presenting with postural tremor, slowly progressive cerebellar ataxia, and psychiatric and behavioral disturbances. This study describes the first case of ATX-FGF/SCA27A linked to a biallelic frameshift variant in the FGF14 gene. Whole-exome sequencing (WES) was conducted using the Illumina NovaSeq 6000 platform, and the identified variant was confirmed using Sanger sequencing. We report the first case of autosomal recessive FGF14-related cerebellar ataxia caused by a c.75del variant resulting in p.Leu26Serfs*51 truncation of the FGF14 protein. This variant was found in a patient born to consanguineous parents and presented with a complex congenital nonprogressive cerebellar disorder accompanied by neurodevelopmental delay, intellectual disability, and prominent drug-responsive paroxysmal non-kinesigenic dyskinesia. Segregation analysis confirmed that the homozygous variant was inherited from heterozygous parents who developed mild gait ataxia and tremor in their 40s. Biallelic loss-of-function variants in FGF14 are a rare cause of inherited cerebellar ataxia and expand the current genetic spectrum of ATX-FGF14. © 2024 International Parkinson and Movement Disorder Society.