A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Oral nitrate supplementation improves cardiovascular risk markers in COPD: ON-BC, a randomised controlled trial.

BACKGROUND: Short-term studies suggest that dietary nitrate (NO3 -) supplementation may improve the cardiovascular risk profile, lowering blood pressure (BP) and enhancing endothelial function. It is not clear if these beneficial effects are sustained and whether they apply in people with COPD, who have a worse cardiovascular profile than those without COPD. Nitrate-rich beetroot juice (NR-BRJ) is a convenient dietary source of nitrate. METHODS: The ON-BC trial was a randomised, double-blind, placebo-controlled parallel group study in stable COPD patients with home systolic BP (SBP) measurement ≥130 mmHg. Participants were randomly allocated (1:1) using computer-generated, block randomisation to either 70 mL NR-BRJ (400 mg NO3 -) (n=40) or an otherwise identical nitrate-depleted placebo juice (0 mg NO3 -) (n=41), once daily for 12 weeks. The primary end-point was between-group change in home SBP measurement. Secondary outcomes included change in 6-min walk distance (6MWD) and measures of endothelial function (reactive hyperaemia index (RHI) and augmentation index normalised to a heart rate of 75 beats·min-1 (AIx75)) using an EndoPAT device. Plasma nitrate and platelet function were also measured. RESULTS: Compared with placebo, active treatment lowered SBP (Hodges-Lehmann treatment effect -4.5 (95% CI -5.9- -3.0) mmHg), and improved 6MWD (30.0 (95% CI 15.7-44.2) m; p<0.001), RHI (0.34 (95% CI 0.03-0.63); p=0.03) and AIx75 (-7.61% (95% CI -14.3- -0.95%); p=0.026). CONCLUSIONS: In people with COPD, prolonged dietary nitrate supplementation in the form of beetroot juice produces a sustained reduction in BP, associated with an improvement in endothelial function and exercise capacity.

ME2 Deficiency Is Associated With Recessive Neurodevelopmental Disorder.

Malate is an important dicarboxylic acid produced from fumarate in the tricarboxylic acid cycle. Deficiencies of fumarate hydrolase (FH) and malate dehydrogenase (MDH), responsible for malate formation and metabolism, respectively, are known to cause recessive forms of neurodevelopmental disorders (NDDs). The malic enzyme isoforms, malic enzyme 1 (ME1) and 2 (ME2), are required for the conversion of malate to pyruvate. To date, there have been no reports linking deficiency of either malic enzyme isoforms to any Mendelian disease in humans. We report a patient presenting with NDD, subtle dysmorphic features, resolved dilated cardiomyopathy, and mild blood lactate elevation. Whole exome sequencing (WES) revealed a homozygous frameshift variant (c.1379_1380delTT, p.Phe460fs*22) in the malic enzyme 2 (ME2) gene resulting in truncated and unstable ME2 protein in vitro. Subsequent deletion of the yeast ortholog of human ME2 (hME2) resulted in growth arrest, which was rescued by overexpression of hME2, strongly supporting an important role of ME2 in mitochondrial function. Our results also support the pathogenicity and candidacy of the ME2 gene and variant in association with NDD. To our knowledge, this is the first report of a Mendelian human disease resulting from a biallelic variant in the ME encoding gene. Future studies are warranted to confirm ME2-associated recessive NDD.

Utility of pan-immune-inflammation value as a predictor of the prognosis of childhood lupus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic inflammatory multisystemic disease. Monitoring disease activity thoughtout the disease course is important for effective management and assessment of disease outcome. OBJECTIVE: To assess whether the pan-immune inflammation value (PIIV) at diagnosis could predict organ involvement and disease activity in childhood SLE (cSLE) patients after 12 months of disease onst. METHODS: This is an observational retrospective multicenter study that comprised cSLE patients seen and followed at the participating centers between January 2010 and December 2022. All patients met the EULAR/ACR-19 criteria, were immunosuppressive drug-naïve at the time of SLE diagnosis and had a minimal follow-up period of 12 months. The data included clinical and laboratory findings and disease activity using the SLEDAI-2K. Receiver operating characteristic (ROC) curves were employed to determine the optimal cut-off value of PIIV and assess its predictive potential for disease activity, and organ involvement. RESULTS: A total of 125 patients (104 female) with a median age of 16.0 (IQR 5.6) years, a median age at disease onset of 10.9 (IQR 3.0) years, and a median disease duration of 4.8 (IQR 5.3) years were included. The most frequent involved organs at diagnosis were hematological (89.6%), musculoskeletal (68.8%), mucocutaneous (63.2%), and renal (58.4%). However, at a 12-month follow-up visit, the most frequent involved organs were renal (40.0%), hematological (39.2%), musculoskeletal (15.2%), and mucocutaneous (10.4%). The median PIIV at diagnosis was 139 (IQR 229.6), while the median SLEDAI was 12 (IQR 6.5) and 3.5 (IQR 7.0) at diagnosis and 12 months, respectively. An optimal PIIV cut-off of 250 was found to be a predicative for disease activity, with a sensitivity of 45% and a specificity of 86%. The study revealed that the PIIV successfully predicted four systems in our cohort of patients. CONCLUSION: Our work suggests the PIIV might be a reasonable predictor for organ involvement and disease activity in newly diagnosed cSLE, though further research, particularly larger studies, is required to validate these findings, especially regarding organ involvement.

Oscillatory positive expiratory pressure therapy in COPD (O-COPD): a randomised controlled trial.

BACKGROUND: Oscillatory positive expiratory pressure (OPEP) devices are intended to facilitate sputum clearance and reduce cough, but there is limited evidence for their effectiveness in COPD, or to guide patient selection. We aimed to assess the impact of OPEP therapy on quality of life and objective measures of cough and sleep disturbance in patients with COPD with regular sputum production. METHODS: We enrolled stable patients with COPD, who reported sputum production every day or most days, into an assessor-blind, parallel-group, randomised controlled trial comparing 3 months of using an Acapella device against usual care (including use of the active cycle of breathing technique). The primary outcome was cough-related quality of life measured using the Leicester Cough Questionnaire (LCQ). Secondary outcomes included fatigue (Functional Assessment of Chronic Illness Therapy, FACIT score) and generic quality of life (EuroQol-5 Dimensions, EQ-5D). In a substudy (n=45), objective monitoring of cough and disturbance/movement during sleep were also available. RESULTS: 122 participants (61/61 OPEP/control) were recruited, 40% female, 17% smokers, FEV1 38 (25-56)% predicted, and age 62±10 years. 103 completed the study (55/48 OPEP/control). Use of OPEP was associated with an improvement in LCQ compared with controls; MD (95% CI) 1.03 (0.71 to 2.10); (p=0.03), FACIT score 4.68 (1.34 to 8.02); (p<0.001) and EQ-5D 4.00 (0.49 to 19.75); (p=0.04). There was also an improvement in cough frequency -60 (-43 to -95) coughs/24 hours (p<0.001), but no statistically significant effect on sleep disturbance was identified. CONCLUSIONS: Regular use of an Acapella device improves symptoms and quality of life in people with COPD who produce sputum daily or most days. TRIAL REGISTRATION NUMBER: ISRCTN44651852.

El-Hattab-Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: Further delineation of the phenotype and genotype.

Homozygous pathogenic variants in WDR45B were first identified in six subjects from three unrelated families with global development delay, refractory seizures, spastic quadriplegia, and brain malformations. Since the initial report in 2018, no further cases have been described. In this report, we present 12 additional individuals from seven unrelated families and their clinical, radiological, and molecular findings. Six different variants in WDR45B were identified, five of which are novel. Microcephaly and global developmental delay were observed in all subjects, and seizures and spastic quadriplegia in most. Common findings on brain imaging include cerebral atrophy, ex vacuo ventricular dilatation, brainstem volume loss, and symmetric under-opercularization. El-Hattab-Alkuraya syndrome is associated with a consistent phenotype characterized by early onset cerebral atrophy resulting in microcephaly, developmental delay, spastic quadriplegia, and seizures. The phenotype appears to be more severe among individuals with loss-of-function variants whereas those with missense variants were less severely affected suggesting a potential genotype-phenotype correlation in this disorder. A brain imaging pattern emerges which is consistent among individuals with loss-of-function variants and could potentially alert the neuroradiologists or clinician to consider WDR45B-related El-Hattab-Alkuraya syndrome.

Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation.

Fucosyltransferase 8 (FUT8) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as "core fucosylation." Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8. The first individual (consanguineous family) was homozygous for c.715C>T (p.Arg239∗), while the second (non-consanguineous family) was compound heterozygous for c.1009C>G (p.Arg337Gly) and a splice site variant c.1259+5G>T. The third individual (consanguineous family) was homozygous for a c.943C>T (p.Arg315∗). Splicing analysis confirmed the c.1259+5G>T resulted in expression of an abnormal FUT8 transcript lacking exon 9. Functional studies using primary fibroblasts from two affected individuals revealed a complete lack of FUT8 protein expression that ultimately resulted in substantial deficiencies in total core fucosylated N-glycans. Furthermore, serum samples from all three individuals showed a complete loss of core fucosylation. Here, we show that loss of function mutations in FUT8 cause a congenital disorder of glycosylation (FUT8-CDG) characterized by defective core fucosylation that phenotypically parallels some aspects of the Fut8-/- knockout mouse. Importantly, identification of additional affected individuals can be easily achieved through analysis of core fucosylation of N-glycans.

Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease.

Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.

Use of oscillatory positive expiratory pressure (OPEP) devices to augment sputum clearance in COPD: a systematic review and meta-analysis.

INTRODUCTION: Oscillating positive expiratory pressure (OPEP) devices are intended to facilitate sputum clearance in chronic obstructive pulmonary disease (COPD), but there is uncertainty as to their place in treatment pathways. We aimed to review the existing literature to establish the evidence base for their use. METHODS: A systematic search of records up to March 2020 was performed on PubMed, CINAHL, Medline (Ovid), Cochrane and Embase to retrieve clinical trials that evaluated the efficacy of OPEP devices in patients with COPD. Two independent reviewers retrieved the titles, abstracts and full texts, and completed the data extraction. RESULTS: Following full-text review of 77 articles, eight (six randomised control trials and 2 cross-over studies) were eligible for inclusion. Pooled analysis showed low-grade evidence that the use of OPEP devices was associated with decreased COPD symptoms and exacerbations (OR 0.37, 95% CI 0.19 to 0.72), and enhanced exercise capacity; 6 min walk distance (mean difference (95% CI), 49.8 m (14.2 m to 85.5 m); p=0.009]). However, studies were mostly short term with the majority having a high risk of bias. The average acceptance, completion and drop-out rates were 82%, 91% and 8%, respectively. CONCLUSION: The use of OPEP devices can have a positive impact in COPD, but confidence in effect sizes is low and there is a need for further, higher quality studies to examine their long-term efficacy in COPD as well as to identify specific patient phenotypes that are more likely to respond. PROSPERO REGISTRATION NUMBER: CRD 42016041835.

Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.

PURPOSE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. METHODS: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. RESULTS: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. CONCLUSION: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.

Further delineation of METTL23-associated intellectual disability.

METTL23 belongs to a family of methyltransferase like proteins (METTL) that transfer methyl group to various substrates. Recently, pathogenic homozygous variants in METTL23 were identified in patients from three families who presented with intellectual disability (ID) and variable dysmorphic features. In this report, we present unpublished phenotypic data from the original family as well as six new subjects from four families who also presented with mild to moderate ID and dysmorphic features, and were found to harbor four previously unpublished homozygous or compound heterozygous variants in METTL23. Our report further supports the role of this gene in autosomal recessive ID and emphasizes the mild but consistent facial features.

Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy.

Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex.

Evaluation of long-term effectiveness of the use of carglumic acid in patients with propionic acidemia (PA) or methylmalonic acidemia (MMA): study protocol for a randomized controlled trial.

INTRODUCTION: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive inborn errors of metabolism characterized by hyperammonemia due to N-acetylglutamate synthase (NAGS) dysfunction. Carglumic acid (Carbaglu®; Orphan Europe Ltd.) is approved by the US Food and Drug Administration (USFDA) for the treatment of hyperammonemia due hepatic NAGS deficiency. Here we report the rationale and design of a phase IIIb trial that is aimed at determining the long-term efficacy and safety of carglumic acid in the management of PA and MMA. METHODS: This prospective, multicenter, open-label, randomized, parallel group phase IIIb study will be conducted in Saudi Arabia. Patients with PA or MMA (≤15 years of age) will be randomized 1:1 to receive twice daily carglumic acid (50 mg/kg/day) plus standard therapy (protein-restricted diet, L-carnitine, and metronidazole) or standard therapy alone for a 2-year treatment period. The primary efficacy outcome is the number of emergency room visits due to hyperammonemia. Safety will be assessed throughout the study and during the 1 month follow-up period after the study. DISCUSSION: Current guidelines recommend conservative medical treatment as the main strategy for the management of PA and MMA. Although retrospective studies have suggested that long-term carglumic acid may be beneficial in the management of PA and MMA, current literature lacks evidence for this indication. This clinical trial will determine the long-term safety and efficacy of carglumic acid in the management of PA and MMA. TRIAL REGISTRATION: King Abdullah International Medical Research Center ( KAIMRC ): (RC13/116) 09/1/2014. Saudi Food and Drug Authority (SFDA) (33066) 08/14/2014. ClinicalTrials.gov (identifier: NCT02426775) 04/22/2015.

Correction to: Expanding the genetic heterogeneity of intellectual disability.

Variant nomenclature discrepancy was identified in the article.

A null mutation in MICU2 causes abnormal mitochondrial calcium homeostasis and a severe neurodevelopmental disorder.

Mitochondrial calcium homeostasis is a tightly controlled process that is required for a variety of cellular functions. The mitochondrial calcium uniporter complex plays a critical role in this process. MICU2 is a major component of the mitochondrial calcium uniporter complex and its deficiency has been shown to impair mitochondrial calcium [Ca2+]m homeostasis although the exact mechanism remains unclear. We used exome sequencing, positional mapping, and functional characterization of MICU2 deficiency to investigate the role of MICU2 in calcium homeostasis. Using combined autozygome/exome analysis, a homozygous truncating mutation in MICU2 was found to fully segregate with a neurodevelopmental disorder in the form of severe cognitive impairment, spasticity, and white matter involvement in a multiplex consanguineous family. Patient-derived MICU2-deficient cells displayed impaired [Ca2+]m homeostasis, with associated increase in mitochondrial sensitivity to oxidative stress, and abnormal regulation of inner mitochondrial membrane potential. This is the first demonstration of MICU2 deficiency in humans, which we suggest causes a distinct neurodevelopmental phenotype secondary to impaired mitochondrial calcium uniporter-mediated regulation of intracellular calcium homeostasis.

Expanding the genetic heterogeneity of intellectual disability.

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

Congenital disorders of glycosylation: The Saudi experience.

We retrospectively reviewed Saudi patients who had a congenital disorder of glycosylation (CDG). Twenty-seven Saudi patients (14 males, 13 females) from 13 unrelated families were identified. Based on molecular studies, the 27 CDG patients were classified into different subtypes: ALG9-CDG (8 patients, 29.5%), ALG3-CDG (7 patients, 26%), COG6-CDG (7 patients, 26%), MGAT2-CDG (3 patients, 11%), SLC35A2-CDG (1 patient), and PMM2-CDG (1 patient). All the patients had homozygous gene mutations. The combined carrier frequency of CDG for the encountered founder mutations in the Saudi population is 11.5 per 10,000, which translates to a minimum disease burden of 14 patients per 1,000,000. Our study provides comprehensive epidemiologic information and prevalence figures for each of these CDG in a large cohort of congenital disorder of glycosylation patients.

Expanded Newborn Screening Program in Saudi Arabia: Incidence of screened disorders.

AIM: To address the implementation of the National Newborn Screening Program (NBS) in Saudi Arabia and stratify the incidence of the screened disorders. METHODS: A retrospective study conducted between 1 August 2005 and 31 December 2012, total of 775 000 newborns were screened from 139 hospitals distributed among all regions of Saudi Arabia. The NBS Program screens for 16 disorders from a selective list of inborn errors of metabolism (IEM) and endocrine disorders. Heel prick dry blood spot samples were obtained from all newborns for biochemical and immunoassay testing. Recall screening testing was performed for Initial positive results and confirmed by specific biochemical assays. RESULTS: A total of 743 cases were identified giving an overall incidence of 1:1043. Frequently detected disorders nationwide were congenital hypothyroidism and congenital adrenal hyperplasia with an incidence of 1:7175 and 1:7908 correspondingly. The highest incidence among the IEM was propionic acidaemia with an incidence rate of 1:14 000. CONCLUSION: The article highlights the experience of the NBS Program in Saudi Arabia and providing data on specific regional incidences of all the screened disorders included in the programme; and showed that the incidence of these disorders is one of the highest reported so far world-wide.

Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies.

PURPOSE: Retinal dystrophies (RD) are heterogeneous hereditary disorders of the retina that are usually progressive in nature. The aim of this study was to clinically and molecularly characterize a large cohort of RD patients. METHODS: We have developed a next-generation sequencing assay that allows known RD genes to be sequenced simultaneously. We also performed mapping studies and exome sequencing on familial and on syndromic RD patients who tested negative on the panel. RESULTS: Our panel identified the likely causal mutation in >60% of the 292 RD families tested. Mapping studies on all 162 familial RD patients who tested negative on the panel identified two novel disease loci on Chr2:25,550,180-28,794,007 and Chr16:59,225,000-72,511,000. Whole-exome sequencing revealed the likely candidate as AGBL5 and CDH16, respectively. We also performed exome sequencing on negative syndromic RD cases and identified a novel homozygous truncating mutation in GNS in a family with the novel combination of mucopolysaccharidosis and RD. Moreover, we identified a homozygous truncating mutation in DNAJC17 in a family with an apparently novel syndrome of retinitis pigmentosa and hypogammaglobulinemia. CONCLUSION: Our study expands the clinical and allelic spectrum of known RD genes, and reveals AGBL5, CDH16, and DNAJC17 as novel disease candidates.Genet Med 18 6, 554-562.

Loss-of-function mutation in RUSC2 causes intellectual disability and secondary microcephaly.

Inherited aberrancies in intracellular vesicular transport are associated with a variety of neurological and non-neurological diseases. RUSC2 is a gene found on chromosome 9p13.3 that codes for iporin, a ubiquitous protein with high expression in the brain that interacts with Rab proteins (GTPases implicated in intracellular protein trafficking). Although mutations in Rab proteins have been described as causing brain abnormalities and intellectual disability, until now no disease-causing mutations in RUSC2 have ever been reported in humans. We describe, to our knowledge for the first time, three patients with inherited homozygous nonsense mutations identified in RUSC2 on whole-exome sequencing. All three patients had central hypotonia, microcephaly, and moderate to severe intellectual disability. Two patients had additional features of early-onset epilepsy and absence of the splenium. This report adds to the ever-expanding landscape of genetic causes of intellectual disability and increases our understanding of the cellular processes underlying this important neurological entity.