Common Pathogenic Variant Research Articles

The Role of Genetics in Cardiovascular Risk Reduction: Findings From a Single Lipid Clinic and Review of the Literature.

Genetic information is not routinely obtained in the management of most lipid disorders or in primary or secondary prevention of cardiovascular disease (CVD). We sought to determine the prevalence of pathogenic variants associated with lipoprotein metabolism or coronary artery disease (CAD) in a single lipid clinic and discuss the future use of genetic information in CVD prevention. Genetic testing was offered to patients with hypertriglyceridemia (defined as pre-treatment fasting triglycerides ≥150 mg/dL), elevated LDL-C (defined as pre-treatment ≥190 mg/dL), low HDL-C (defined as ≤40 mg/dL), elevated lipoprotein (a) (defined as ≥50 mg/dL or 100 nmol/L) or premature CAD (defined as an acute coronary syndrome or revascularization before age 40 years in men and 50 years in women) using next-generation DNA sequencing of 327 exons and selected variants in 129 genes known or suspected to be associated with lipoprotein metabolism or CAD. 82 of 84 patients (97.6%) were found to have a variant associated with abnormal lipid metabolism or CAD. The most common pathogenic or likely pathogenic variants included those of the LDL receptor (15 patients) and lipoprotein lipase (9 patients). Other common variants included those of apolipoprotein A5 (14 patients) and variants associated with elevated lipoprotein (a) (25 patients). The majority of patients presenting to a single lipid clinic were found to have at least one variant associated with abnormal lipoprotein metabolism or CAD. Incorporating genetic information, including the use of genetic risk scores, is anticipated in the future care of lipid disorders and CVD prevention.

Kawasaki disease and familial mediterranean fever gene mutations, is there any link?

Background and aim: Kawasaki disease (KD) is an acute febrile, self-limiting, and systemic vasculitis of unknown etiology. MEFV gene has a major role in autoinflammatory disorders and innate immune reactions. Several reports revealed that MEFV gene mutations are associated with systemic vasculitis. The aim of this study was to determine the association between KD and MEFV gene mutations.Methods: The peripheral blood of 30 patients who were diagnosed with KD based on ACC criteria and 224 healthy people as a control group (113 male and 111 female), were collected and the samples screened for the 12 common pathogenic variants according to manufacturer’s instructions.Results: The mean age of patients (13 females and 17 males) was 7.7 years. Ten percent of patients showed a mutation, that was meaningfully (p<0.05%) lower than that of healthy controls (25%). E148Q was shown in two patients and compound heterozygous (E148Q-M680I) was detected in one of them with lack of FMF presentations. No significant and meaningful associations were detected between the MEFV gene variant alleles and KD.Conclusion: Unlike in other types of pediatric vasculitis, this study did not reveal any significant association between the MEFV gene mutations and KD, moreover, because of the lower frequency of mutations in these patients, it seems that this gene has a modifier and/or protective role in KD.

Novel, rare and common pathogenic variants in the CFTR gene screened by high-throughput sequencing technology and predicted by in silico tools

Cystic fibrosis (CF) is caused by ~300 pathogenic CFTR variants. The heterogeneity of which, challenges molecular diagnosis and precision medicine approaches in CF. Our objective was to identify CFTR variants through high-throughput sequencing (HTS) and to predict the pathogenicity of novel variants through in 8 silico tools. Two guidelines were followed to deduce the pathogenicity. A total of 169 CF patients had genomic DNA submitted to a Targeted Gene Sequencing and we identified 63 variants (three patients had three variants). The most frequent alleles were: F508del (n = 192), G542* (n = 26), N1303K (n = 11), R1162* and R334W (n = 9). The screened variants were classified as follows: 41 – pathogenic variants [classified as (I) n = 23, (II) n = 6, (III) n = 1, (IV) n = 6, (IV/V) n = 1 and (VI) n = 4]; 14 – variants of uncertain significance; and seven novel variants. To the novel variants we suggested the classification of 6b-16 exon duplication, G646* and 3557delA as Class I. There was concordance among the predictors as likely pathogenic for L935Q, cDNA.5808T>A and I1427I. Also, Y325F presented two discordant results among the predictors. HTS and in silico analysis can identify pathogenic CFTR variants and will open the door to integration of precision medicine into routine clinical practice in the near future.

The landscape of Parkin variants reveals pathogenic mechanisms and therapeutic targets in Parkinson's disease.

Mutations in Parkin (PARK2), which encodes an E3 ubiquitin ligase implicated in mitophagy, are the most common cause of early-onset Parkinson's disease (EOPD). Hundreds of naturally occurring Parkin variants have been reported, both in Parkinson's disease (PD) patient and population databases. However, the effects of the majority of these variants on the function of Parkin and in PD pathogenesis remain unknown. Here we develop a framework for classification of the pathogenicity of Parkin variants based on the integration of clinical and functional evidence-including measures of mitophagy and protein stability and predictive structural modeling-and assess 51 naturally occurring Parkin variants accordingly. Surprisingly, only a minority of Parkin variants, even among those previously associated with PD, disrupted Parkin function. Moreover, a few of these naturally occurring Parkin variants actually enhanced mitophagy. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. Together, the findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets to stratify patients for genotype-specific drug design.

Unraveling incontinentia pigmenti: A comparison of phenotype and genotype variants

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that affects multiple systems with highly variable phenotypic expressivity. Although most affected individuals carry a common pathogenic variant on the IKBKG gene, approximately 20% have no identifiable mutation. To describe clinical characteristics and genotype of IP patients and compare clinical differences between IKBKG pathogenic variant positive and negative cohorts. Retrospective cohort study conducted at a large tertiary pediatric center from 1990 to 2017, for children with a clinical diagnosis of IP. Forty-two children with IP were identified, including 33 of 42 (79%) females. Most presented with cutaneous stage I findings (31 of 42; 74%). Extracutaneous involvements were common: dental (50%), ocular (31%), hair (31%), nail (15%), and neurodevelopmental (26%). An IKBKG pathogenic variant was detected in 20 of 34 (59%) patients. Compared with these, 14 of 34 (41%) patients who tested negative were significantly more likely (P<.05) to be male, have no family history of IP, and have lower incidences of dental and hair anomalies. Retrospective methodology limits clear determination of the temporality of symptoms. Clinical differences between IKBKG pathogenic variant positive and negative IP cohorts support the prognostic utility of molecular genetic evaluation.

CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype–phenotype correlation. Methods: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype–phenotype correlation. Results: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients’ stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype–phenotype correlation (80%). Conclusion: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype–phenotype correlation observed.

Germline DNA repair mutations in men with prostate cancer are less frequent in African Americans as compared with Caucasians.

258 Background: Pathogenic DNA repair defects are well described in Caucasian (C) men with prostate cancer (PCa) but comparative data on African-American (AA) men are sparse. Methods: Germline testing for DNA repair defects were assayed by Invitae (Invitae.com). Pathogenic variants in 14 genes were compared between AA and C men with PCa; these particular genes were also assessed by Pritchard et al NEJM 375:443, 2016. Identical gene panels were not used in all men, thus variations in assay numbers from gene to gene are noted. Chi square was used to compare proportions. Results: In the 14 genes, there were 16/214 (7.5%) AA men and 347/2488 (13.9%) C men with pathogenic findings (p=0.008). As shown in the Table, the most common pathogenic variants in AA men were BRCA2 (6/214, 2.8%), BRCA1 (3/213, 1.4%), PALB2 (2/182, 1.1%), ATM (2/206, 1.0%), RAD51C (1/148, 0.68%), CHEK2 (1/207, 0.48%), and PMS2 (1/212, 0.47%). In contrast to C men in this series, no AA men had pathogenic mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Pathogenic CHEK2 was less commonly detected in AA as compared to C (p=0.03) in this dataset. Comparing our C men revealed no differences in the proportion of men with pathogenic findings compared to Pritchard et al (13.9% here vs 11.8%, P=0.15). Conclusions: AA men with PCa are less likely to have pathogenic DNA repair mutations among these 14 assayed DNA repair genes compared to C men. Limitations regarding lack of stage, Gleason scores, and FH are notable. Details on gene assays and comparison to Pritchard et al NEJM 375:443, 2016 [Table: see text]

Clinical characteristics of men with prostate cancer and evaluation of NCCN prostate cancer guidelines on germline genetic testing outcomes.

252 Background: Growing evidence suggests up to 12% of men with metastatic prostate cancer (PC) harbor a pathogenic variant (PV) in genes associated with hereditary cancer risk. Updated NCCN PC guidelines include consideration for germline testing (GT) in men with high risk, very high risk, regional, or metastatic PC. As a result, we expanded our criteria for GT in men with PC to include these groups and men with a strong family history for PC beginning in January 2018. This study reports the clinical characteristics and germline findings before and after this expansion. Methods: Men with PC underwent multi-gene genetic testing (GT) for PVs from June 2016-June 2018 with genetic counselors. Clinical information and germline GT results were analyzed. Results: Of 285 eligible men who met with a genetic counselor, there were 201 evaluable GT results. One PV was excluded for suspicion of clonal hematopoiesis of indeterminate potential. Twenty-seven PVs were identified in 24 men (12.4%). Three men had two PVs identified (1.5%), at least one PV of which was in ATM or BRCA2. The most common PVs were ATM (n = 6, 3.0%), BRCA2 (n = 7, 3.5%), MYH (n = 4, 2.0%), and HOXB13 (n = 4, 2.0%). Rate of PVs were not statistically different across the two timeframes of GT, (2016-17, 14%; 2018, 11.2%; p = 0.60). PVs were not statistically associated with a higher ISUP group (1-3: 10.1%, 4-5: 13.6%; p = 0.49) and were distributed across multiple NCCN risk groups. Almost all men tested reported a family history of cancer, with the most frequent cancers reported including PC (n = 79, 39.3%), breast (n = 55, 27.4%), and colon cancer (n = 23, 11.4%). Family history of PC was not statistically associated with genetic test results (PV: 54%, no PV: 37%; p = 0.11). Conclusions: Expanding germline GT criteria will substantially increase patient volume without significant changes to the PV rate. Higher PC risk defined by ISUP or NCCN was not associated with the rate of PVs. Given this finding, further broadening the criteria for GT in PC may be warranted.

Direct-to-consumer raw genetic data and third-party interpretation services: more burden than bargain?

The latest response to consumers’ increased demand for accessible genetic health information is the US Food and Drug Administration (FDA)’s recent approval of 23andMe’s direct-to-consumer (DTC) genetic test for the three common BRCA1 and BRCA2 pathogenic variants found in the Ashkenazi Jewish population.1 23andMe and other DTC genetic testing companies officially report out ancestry, trait, and some health information, while also providing consumers with files of their raw genetic data. Up to 62% of consumers use third-party applications to interpret the raw data and health information not included in companies’ reports.2 Little data exists on the nature and prevalence of clinical follow up of third-party raw genetic data interpretation, nor on the psychosocial impact on the consumer and their families.3 This information is of timely importance as a recent study suggests that 40% of genetic variations within DTC raw data sent for clinical confirmation are false positives.4 This raises many questions about the impact of DTC genetic testing and third-party interpretation tools, including the appropriate use of healthcare resources, clinical utility, provider and patient understanding of limitations, and psychological impact on consumers. In this commentary, we present four case vignettes from cardiovascular genetics clinics to bring awareness to possible harms of DTC raw data interpretation. Future studies investigating the breadth and frequency of cases such as these are required to understand the scope of this harm.

GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome

Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders.

Identification of a rare homozygous &lt;i&gt;SZT2&lt;/i&gt; variant due to uniparental disomy in a patient with a neurodevelopmental disorder

Because biallelic SZT2 variants have been reported in patients with neurodevelopmental disorders associated with various degrees of developmental delay, intractable seizures, and distinctive features; this condition is recognized as an autosomal recessive disorder. Previously, eleven patients have been reported and most of them have compound heterozygous SZT2 variants, leading to premature termination. In these patients, all reported variants were unique and there were no common pathogenic variants identified. In this study, we identified a paternal uniparental disomy of chromosome 1 in a patient with a neurodevelopmental disorder associated with severe intellectual disability, intractable epilepsy, autistic features, distinctive features, and transient macrocephaly. This resulted in homozygous patterns through chromosome 1. Among the variants in chromosome 1, a rare SZT2 variant, NM_015284.3:c.6553C>T (p.Arg2185Trp), was selected as a powerful candidate variant in this patient. Although the clinical features of this patient are relatively milder than that reported previously, it may be derived from genetic heterogeneity. This is the first report of a homozygous missense SZT2 variant.

MYOFIBRILLAR AND DISTAL MYOPATHIES: P.254Pyroxd1 mutations cause recessive adult-onset slowly progressive LGMD

Limb-girdle muscular dystrophy (LGMD) is a group of inherited muscle diseases with slowly progressive, predominantly proximal myopathy. The phenotype of LGMD ranges from mild late-onset to severe early-onset disease. At least 31 different genes have been implicated in LGMD. Mutations in PYROXD1 gene was recently reported to cause recessive muscle disease. The described phenotype of PYROXD1 disease was congenital myofibrillar myopathy with symptom onset between infancy and 8 years. Internalized nuclei and myofibrillar disorganization were described as specific histopathologic features. We report on four Finnish patients, of whom two are siblings, with homozygous or compound heterozygous variants in PYROXD1 underlying adult-onset LGMD. Three of our patients were homozygous for the previously described variant p.Asn155Ser, and presented with muscle weakness in their teens or early thirties but have remained ambulant to over 60 years of age. Our fourth patient was compound heterozygous for the p.Asn155Ser variant and a previously unknown variant p.Tyr354Cys. He had the onset of proximal muscle weakness as late as aged 49 years. Thus the disease onset in our patients, particularly in the compound heterozygous patient, was considerably later than in the previously reported individuals with PYROXD1 mutations. Muscle biopsies showed dystrophic changes, excess of fat and fibrosis, necrosis and atrophy but no clear myofibrillar aggregates that would be consistent with myofibrillar myopathy. On muscle MRI the most severe fatty degenerative change was seen in gluteal region and anterior compartment of the thigh with relative sparing of rectus femoris. Our results show that p.Asn155Ser is a common pathogenic PYROXD1 variant, leading to myopathy with highly variable ages of disease onset. These findings extend the phenotypes caused by PYROXD1 mutations to adult-onset LGMD.

Congenital Myasthenic Syndrome: Spectrum of Mutations in an Indian Cohort.

To investigate the mutational spectrum and genotype-phenotype correlation in Indian patients with congenital myasthenic syndrome (CMS), using next-generation sequencing of 5 genes. CHRNE, COLQ, DOK7, RAPSN, and GFPT1 were sequenced in 25 affected patients. We found clinically significant variants in 18 patients, of which variants in CHRNE were the most common, and 9 were novel. A common pathogenic COLQ variant was also detected in 4 patients with isolated limb-girdle congenital myasthenia. Targeted screening of 5 genes is an effective alternate test for CMS, and an affordable one even in a developing country such as India. In addition, we recommend that patients with isolated limb-girdle congenital myasthenia be screened initially for the common COLQ pathogenic variant. This study throws the first light on the genetic landscape of CMSs in India.

Worldwide distribution of common IDUA pathogenic variants.

Mucopolysaccharidosis type I (MPS I) is a rare disorder caused by deleterious sequence variants in the α-L-iduronidase (IDUA) gene. More than 200 pathogenic variants have been described so far, but their frequencies have not yet been analyzed on a worldwide scale. To address this, we analyzed the genotypes of MPS I patients from 35 published studies papers. The most common pathogenic variant observed was p.Trp402Ter. With frequencies of up to 63%, it was the major allele in most European countries, America and Australia. The variant p.Gln70Ter was also frequent; it was found mainly in Northern and Eastern Europe. The most frequent variant in North African countries was p.Pro533Arg; in Morocco, it represented more than 90% of mutant alleles. Variants observed in East Asians were not found in Western populations, including c.1190-1G>A, p.Ala79Val, p.Leu346Arg and c.613_617dupTGCTC. Conversely, p.Trp402Ter and p.Pro533Arg were not found in patients from East Asia. In conclusion, the most common pathogenic IDUA variant in MPS I patients are p.Trp402Ter, p.Gln70Ter and p.Pro533Arg. Knowledge about the genetic background of MPS I for each population is essential when developing new genotype-targeted therapies, as well as to enable faster genetic analysis and improve patient management.

Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy.

MPV17-related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non-consanguineous Black South African heritage. Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in 2 unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122-1/38) with an estimated newborn incidence of 1 in 18 496 (95% CI; 1/59 536-1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterized severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found.

Genotypes of patients with phenylalanine hydroxylase deficiency in the Wisconsin Amish

In the Plain Community, there is an increased frequency of genetic disorders including phenylalanine hydroxylase (PAH) deficiency. Common pathogenic variants have been observed due to founder effect and closed community. This study obtained genotypes of 12 Plain individuals with PAH deficiency, identified through newborn screen or diagnosed by symptomatic presentation, who are receiving medical care at the University of Wisconsin metabolic clinic. Genotype and phenotypic data were evaluated to characterize genotype-phenotype correlations. Results can inform the need for confirmatory testing for the disorder and provide a better understanding of the biochemical phenotype, which may help with management.

SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency.

Recessive mutations in the mitochondrial copper-binding protein SCO2, cytochrome c oxidase (COX) assembly protein, have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency. Significantly expanding the known phenotypic spectrum, we identified compound heterozygous variants in SCO2 in two unrelated patients with axonal polyneuropathy, also known as Charcot-Marie-Tooth disease type 4. Different from previously described cases, our patients developed predominantly motor neuropathy, they survived infancy, and they have not yet developed the cardiomyopathy that causes death in early infancy in reported patients. Both of our patients harbour missense mutations near the conserved copper-binding motif (CXXXC), including the common pathogenic variant E140K and a novel change D135G. In addition, each patient carries a second mutation located at the same loop region, resulting in compound heterozygote changes E140K/P169T and D135G/R171Q. Patient fibroblasts showed reduced levels of SCO2, decreased copper levels and COX deficiency. Given that another Charcot-Marie-Tooth disease gene, ATP7A, is a known copper transporter, our findings further underline the relevance of copper metabolism in Charcot-Marie-Tooth disease.

The adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent-onset POLG-related mitochondrial disease.

SummaryFocal status epilepticus in POLG‐related mitochondrial disease is highly refractory to pharmacological agents, including general anesthesia. We report the challenges in managing a previously healthy teenager who presented with de novo epilepsia partialis continua and metabolic stroke resulting from the homozygous p.Ala467Thr POLG mutation, the most common pathogenic variant identified in the Caucasian population. We applied transcranial direct current stimulation (tDCS; 2 mA; 20 min) daily as an adjunctive therapy because her focal seizures failed to respond to five antiepileptic drugs at maximal doses. The electrical and clinical seizures stopped after 3 days of tDCS. The second course of tDCS was administered for 14 days when the focal seizures re‐emerged a month later. The patient tolerated the procedure well. Following 4 months of hospitalization and prolonged community rehabilitation, our patient has now returned to full‐time education with support, and there is no report of cognitive deficit. We have demonstrated the safety and efficacy of tDCS in treating refractory focal motor seizures caused by mitochondrial disease.

ISCA2 Related Mitochondrial Disorder: A distinct cause of Infantile Leukodystrophy

Introduction: Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process in the mitochondria. It is required to produce various ISC-containing proteins which are present in the nucleus, mitochondria, and cytosol. ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid. ISCA2 encodes an A-type ISC protein involved in the assembly of mitochondrial iron-sulfur cluster (4Fe- 4S) which is important for electron transfer and mitochondrial function. ISCA2 related Mitochondrial Disorder (IRMD) is a severe disorder of systemic energy metabolism, characterized by weakness, respiratory failure, lack of neurological development, lactic acidosis, hyperglycinemia and early death. ISCA2 gene is located on Chromosome 14q24.3 and has autosomal recessive inheritance. Objective: In this report, we present the clinical and radiological features a subject homozygous for the common founder pathogenic variant; c.229G>A; p.Gly77Ser. Conclusion: IRMD presents with infantile onset triad of progressive neurodevelopmental regression, nystagmus and optic atrophy. It is a rapidly progressive condition with death usually in first two years of life. It should be considered in infantile onset leukodystrophy. Future studies are needed to understand the role of ISCA2 gene, the effect of its mutation, and any targets for future treatment strategies.

Periventricular nodular heterotopia and bilateral intraventricular xanthogranulomas in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) is the most common pathogenic copy number variant in humans. Neuropsychiatric phenotypes, including schizophrenia, are prominent. Imaging studies of individuals with this syndrome show a variety of abnormalities that may indicate abnormal neuronal migration. Here we present the neuroimaging and neuropathologic features of a 22q11DS patient with bilateral periventricular nodular heterotopias (PNH) and intraventricular xanthogranulomas that were identified by post-mortem examination.