Biallelic XPR1 mutation associated with primary familial brain calcification presenting as paroxysmal kinesigenic dyskinesia with infantile convulsions

BackgroundMutations in the XPR1 gene are associated with primary familial brain calcifications (PFBC). All reported mutations are missense and inherited as an autosomal dominant trait. PFBC patients exhibited movement disorders, neuropsychiatric symptoms, and other associated symptoms with diverse severity, even within the same family.Materials and methodsWe identified and enrolled a patient with PFBC. Clinical data were comprehensively collected, including the age of onset, seizure types and frequency, trigger factors of paroxysmal dyskinesia, response to drugs, and general and neurological examination results. Whole-exome sequencing (WES) was performed to detect pathogenic variants. We further systematically reviewed the phenotypic and genetic features of patients with XPR1 mutations.ResultsThe patient showed bilateral calcification involving basal ganglia and cerebellar dentate. Clinically, he presented as paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) with favorable outcome. We identified a compound heterozygous XPR1 mutation (c.786_789delTAGA/p.D262Efs*6, c.1342C>T/p.R448W), which were inherited from unaffected parents respectively. Further literature review shows a wide range of clinical manifestations of patients with XPR1 mutations, with movement disorders being the most common.ConclusionsThis is the first report of biallelic mutations in XPR1. The findings suggest for the first time a possible link between PKD/IC and XPR1 mutations.     

Integrating whole-genome sequencing and transcriptomic findings in the diagnosis and management of Coffin-Siris syndrome

IntroductionAlthough the whole-exome sequencing (WES) approach has been widely used in clinic, many rare diseases with syndromic and nonsyndromic neurological manifestations remain undiagnosed. Coffin-Siris syndrome (CSS) is a rare autosomal dominant genetic disease characterized by neurodevelopmental delay. A suspected diagnosis can be made based on the typical CSS clinical features; however, molecular genetic testing is necessary for a confirmed diagnosis.ObjectivesThree CSS-like patients with negative results in the WES and chromosomal microarray analysis (CMA) were recruited in this study.MethodsWe used whole-genome sequencing (WGS) technology to sequence the peripheral blood of the three families. To further explore the possible pathogenesis of CSS, we performed RNA-sequencing (RNA-seq).ResultsWGS identified the three CSS patients were carrying de novo copy number variants of the ARID1B gene, which have not been reported before. RNA-seq identified 184 differentially expressed genes (DEGs), with 116 up-regulated and 68 down-regulated. Functional annotation of DEGs showed that two biological processes (immune response, chemokine activity) and two signaling pathways (cytokine-cytokine receptor interaction, chemokine activity) were highlighted. We speculated that ARID1B deficiency might trigger abnormal immune responses, which may be involved in the pathophysiologic mechanisms of CSS.ConclusionOur research provided further support for WGS application in CSS diagnosis and made an investigational approach for the underlying mechanisms of CSS.     

A case of ALG11-congenital disorders of glycosylation diagnosed by post-mortem whole exome sequencing

IntroductionCongenital disorders of glycosylation (CDG) are inherited inborn errors of metabolism due to abnormal protein and lipid glycosylation that present with multi-systemic manifestations. The heterogeneity of CDG poses a serious diagnostic challenge; therefore, whole-exome sequencing (WES), which plays an increasingly important role in the molecular diagnosis of CDG, is used for examining patients with CDG.Case reportWe report the case of a two-month-old male patient who developed developmental and epileptic encephalopathy (DEE) with intractable seizures and microcephaly. EEG demonstrated a suppression-burst (S-B) pattern, and MRI showed delayed myelination and progressive atrophic changes. Although CDG was clinically suspected, serum transferrin isoelectric focusing analysis appeared to be normal. The patient died by six years of age. Postmortem WES performed approximately 20 years after the patient’s death revealed homozygous variants in ALG11 (NM_001004127.3: c.935A > C, p.Glu312Ala), and the patient was diagnosed with ALG11-CDG.ConclusionWe present a case of the patient with ALG11-CDG diagnosed using post-mortem WES. The EEG revealed a S-B pattern that indicated severely drug-resistant DEE, which was associated with poor prognosis. If a CDG is suspected, WES should be considered.     

A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay

IntroductionHypomyelinating leukodystrophies (HLDs) are genetically heterogeneous syndromes, presenting abnormalities in myelin development in the central nervous system. Recently, a recurrent de novo mutation in TMEM106B was identified to be responsible for five cases of HLD. We report the first Japanese case of TMEM106B gene mutation.Case StudyA 3-year-old patient presented with nystagmus and muscle hypotonia in his neonatal period, followed by delayed psychomotor development. Brain magnetic resonance images showed delayed myelination. Wave III and subsequent components were not presented by his auditory brainstem response. These features were similar to those observed in Pelizaeus-Merzbacher disease (PMD).MethodsProteolipid protein 1 (PLP1) gene screening, Mendelian disease panel exome, and whole-exome sequencing (WES) were sequentially performed.ResultsAfter excluding mutations in either PLP1 or other known HLD genes, WES identified a mutation c.754G > A, p.(Asp252Asn) in TMEM106B, which appeared to occur de novo, as shown by Sanger sequencing and SalI restriction enzyme digestion of PCR products.DiscussionThis is the sixth case of HLD with a TMEM106B mutation. All six cases harbored the same variant. This specific TMEM106B mutation should be investigated when a patient shows PMD-like features without PLP1 mutation. Our PCR-SalI digestion assay may serve as a tool for rapid HLD diagnosis.     

Molecular Genetic Diagnosis of a Bethlem Myopathy Family with an Autosomal-Dominant COL6A1 Mutation,as Evidenced by Exome Sequencing

BackgroundWe describe herein the application of whole exome sequencing (WES) for the molecular genetic diagnosis of a large Korean family with dominantly inherited myopathy.ConclusionsThis is the first report of identification of COL6A1-mediated Bethlem myopathy in Korea, and indicates the utility of WES for the diagnosis of muscular dystrophy.     

A novel de novo TET3 loss-of-function variant in a Turkish boy presenting with neurodevelopmental delay and electrical status epilepticus during slow-wave sleep

BackgroundBeck-Fahrner syndrome is caused by homozygous or heterozygous mutations in TET3 on chromosome 2p13. The general characteristics of this syndrome include behavioral abnormalities such as autistic features, attention-deficit hyperactivity disorder, learning disabilities, and epilepsy.Case presentationSix years old male patient was found to have a de novo TET3 loss-of-function variant by whole-exome sequencing (WES) analysis and was diagnosed with electrical status epilepticus during slow-wave sleep (ESES) based on clinical and electroencephalogram (EEG) characteristics. The patient had a neurodevelopmental delay from the age of 3 months and started experiencing generalized tonic–clonic seizures and regression at the age of 5 years. EEG findings were consistent with ESES, and WES analysis revealed a novel heterozygous nonsense NM_001366022.1:c.1594C > T (p.Arg532*) variant in TET3. Valproic acid and immunotherapy were administered for the first 6 months, and clobazam was administered orally in addition to oral valproic acid therapy for the next 6 months. Clinical improvement was noted regardless of EEG improvement for the first 6 months. EEG improvement was achieved with clobazam. No regression was observed following the discontinuation of immunotherapy.ConclusionDecreased TET3 enzyme activity may be one of the new genetic etiologies of ESES.     

Exome sequencing detects compound heterozygous nonsense LAMA2 mutations in two siblings with atypical phenotype and nearly normal brain MRI

LAMA2 mutations cause the most frequent congenital muscular dystrophy subtype MDC1A and a variety of milder phenotypes, characterized by total or partial laminin-α2 deficiency. In both severe and milder cases brain MRI invariably shows abnormal white matter signal intensity. We report clinical, histopathological, imaging and genetic data on two siblings with very subtle, and at first undetected, reduction in laminin-α2 expression, and brain MRI showing minor non-specific abnormalities. Clinical features in the female proband were characterized by muscle weakness involving neck and axial muscles, and pelvic girdle and distal lower limb muscles, reduced tendon reflexes and pes cavus. Clinical features in a younger brother were similar, and remained stable in both siblings during the follow up. Whole exome sequencing (WES) detected two heterozygous truncating LAMA2 mutations. Brain MRI in combination with laminin-α2 immunohistochemistry might not be sufficient and WES might be the only means to reach a diagnosis.     

A Compound Heterozygous Pathogenic Variant in B4GALNT1 Is Associated With Axonal Charcot-Marie-Tooth Disease

Background and PurposePathogenic variants in B4GALNT1 have been reported to cause hereditary spastic paraplegia 26. This study has revealed that a novel compound heterozygous pathogenic variant in B4GALNT1 is associated with axonal Charcot-Marie-Tooth disease (CMT).MethodsWhole-exome sequencing (WES) was used to identify the causative factors and characterize the clinical features of a Korean family with sensorimotor polyneuropathy. Functional assessment of the mutant genes was performed using a motor neuron cell line.ResultsThe WES revealed a compound heterozygous pathogenic variant (c.128dupC and c.451G>A) in B4GALNT1 as the causative of the present patient, a 53-year-old male who presented with axonal sensorimotor polyneuropathy and cognitive impairment without spasticity. The electrodiagnostic study showed axonal sensorimotor polyneuropathy. B4GALNT1 was critical to the proliferation of motor neuron cells. The compensation assay revealed that the pathogenic variants might affect the enzymatic activity of B4GALNT1.ConclusionsThis study is the first to identify a case of autosomal recessive axonal CMT associated with a compound heterozygous pathogenic variant in B4GALNT1. This finding expands the clinical and genetic spectra of peripheral neuropathy.     

Homozygosity mapping and whole exome sequencing provide exact diagnosis of Cohen syndrome in a Saudi family

BackgroundCohen syndrome (CS) is a rare multi-system autosomal recessive disorder with a high prevalence in the Finnish population. Clinical features of Finnish-type CS are homogeneous, however, in non-Finnish populations, CS diagnosis is challenging due to broad phenotypic variability.MethodsWe studied a consanguineous family having three affected individuals with clinical features of severe intellectual disability and global developmental delay. Clinical diagnosis of the phenotype could not be established based on the features. Therefore, whole genome SNP genotyping and whole exome sequencing (WES) were performed on DNA samples from affected and unaffected family members.ResultsHomozygosity mapping identified a shared loss of heterozygosity region on chromosome 8q22.1-q22.3 and WES data analysis revealed an insertion-deletion (indel) mutation (c.11519_11521delCAAinsT) in the VPS13B gene. The indel is predicted to cause a frameshift resulting in a premature termination of the VPS13B protein (NP_060360.3:p.Pro3840Leufs*2).ConclusionVPS13B encodes a giant transmembrane protein called vacuolar protein sorting 13 homolog B. VPS13B is known to play a role in the glycosylation of Golgi proteins and in endosomal-lysosomal trafficking. Moreover, it is thought to function in vesicle mediated transport and sorting of proteins within the cell. The mechanism by which abnormalities of the VPS13B protein lead to the phenotype of CS is currently unknown. Here, in this study, we successfully established a clinical diagnosis of CS cases from a family using genomic analyses. Clinical re-examination of the patients revealed characteristic ocular abnormalities.     

Small mutation screening in the DMD gene by whole exome sequencing of an Argentine Duchenne/Becker muscular dystrophies cohort

Dystrophinopathies are neuromuscular X-linked recessive diseases caused by mutations in the DMD gene. This study aimed to identify DMD gene small mutations by Whole Exome Sequencing (WES), in order to confirm clinical diagnosis, identify candidates for Ataluren treatment and perform carrier status testing. Furthermore, was our goal to characterize the DMD sequence variants and identify ancestral haplotypes. We analyzed 40 non-related individuals (38 affected boys with dystrophinopathy presumptive clinical diagnosis and 2 at-risk women) with negative MLPA results. Pathogenic DMD variants were found in 32 boys. Surprisingly, in another 4 patients with absence/deficiency of dystrophin in muscle biopsy, pathogenic variants were found in Limb-girdle muscular dystrophy genes. Therefore, the WES detection rate resulted ∼94% (36/38). We could identify 15 Ataluren candidates and exclude 2 at-risk women. The characterization of the occurrence and diversity of DMD sequence variants from our cohort and from LOVD database, revealed no hotspots but showed exons/introns unlikely to carry small molecular alterations and exons presenting a greater mutagenic abundance than others. Also, we have detected the existence of 2 co-segregating haplotypes blocks. Finally, this work represents the first DMD gene small mutations screening applying WES in an argentine cohort, contributes with the characterization of our population and collaborates with the DMD small mutation’s knowledge.     

Single-fiber electromyography-based diagnosis of CACNA1A mutation in children: A potential role of the electrodiagnosis in the era of whole exome sequencing

IntroductionA loss-of-function mutation in CACNA1A, which encodes P/Q-type Ca channels, causes various diseases. As most of the Ca channels at neuromuscular junctions are of the P/Q type, patients with loss-of-function CACNA1A mutations exhibit disturbed neuromuscular transmission. The associated jitters and blocking in such patients can be detected by single-fiber electromyography (SFEMG).CasesWe report two cases with different phenotypes, which were predicted to harbor loss-of-function mutations of CACNA1A, by using axonal stimulation SFEMG. One case involved a 2-year-old boy with episodic ataxia type 2. The other case involved a 7-year-old girl diagnosed with epileptic encephalopathy. SFEMG results revealed jitters and blocking in both cases. Moreover, whole exome sequencing (WES) revealed a heterozygous CACNA1A mutation, c.5251C>T, p.Arg1751Trp, in the former case and a novel de novo CACNA1A mutation, c.2122G>A, p.Val708Met, in the latter.ConclusionsOur cases indicate that SFEMG is a potentially useful diagnostic tool for patients with CACNA1A mutation, especially in pediatric cases where trio analysis is difficult or novel mutations are present.     

Dravet syndrome: patients with co-morbid SCN1A gene mutations and mitochondrial electron transport chain defects

PurposeTo review our cohort of patients with Dravet syndrome and determine if patients with SCN1A mutations can also express mitochondrial disease due to electron transport chain dysfunction.MethodsA retrospective chart review was used to describe clinical manifestations and retrieve biochemical testing, neuroimaging, gene sequencing, and electroencephalographic results of patients expressing both mitochondrial disease and Dravet syndrome.ResultsTwo children were found to have pathological mutations in the SCN1A gene and defects in mitochondrial electron transport chain complex activity. Both developed early febrile and medically intractable afebrile seizures with resulting neurocognitive decline. In the first patient, a muscle biopsy demonstrated complex IV dysfunction and in the second patient, complex III dysfunction. Patient 1 had more difficult to control seizures, and had features consistent with severe autism. Patient 2, who had earlier control and less severe seizures, did not have features of autism. Patient 1 had SCN1A missense mutation, c. 3734 G > A and patient 2 had a mutation, c. 3733 C > T, which produces a truncation mutation.ConclusionOur two patients underscore the need to rule out possible co-morbid mitochondrial disease and Dravet syndrome. The treatment of seizures for each is different, with valproic acid being first line treatment in Dravet syndrome and contraindicated in many mitochondrial diseases, due to possible induction of liver failure and death. Failure to pursue complete diagnostic evaluation might influence medication choice, possible seizure control, and developmental outcomes.     

Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges

Inherited peripheral neuropathies (IPN) are one of the most frequent inherited causes of neurological disability characterized by considerable phenotypic and genetic heterogeneity. Based on clinical and electrophysiological properties, they can be subdivided into three main groups: HMSN, dHMN, and HSN. At present, more than 50 IPN genes have been identified. Still, many patients and families with IPN have not yet received a molecular genetic diagnosis because clinical genetic testing usually only covers a subset of IPN genes. Moreover, a considerable proportion of IPN genes has to be identified. Here we present results of WES in 27 IPN patients excluded for mutations in many known IPN genes. Eight of the patients received a definite diagnosis. While six of these patients carried bona fide pathogenic mutations in known IPN genes, two patients had mutations in genes known to be involved in other types of neuromuscular disorders. A further group of eight patients carried sequence variations in IPN genes that could not unequivocally be classified as pathogenic. In addition, combining data of WES and linkage analysis identified SH3BP4, ITPR3, and KLHL13 as novel IPN candidate genes. Moreover, there was evidence that particular mutations in PEX12, a gene known to cause Zellweger syndrome, could also lead to an IPN phenotype. We show that WES is a useful tool for diagnosing IPN and we suggest an expanded phenotypic spectrum of some genes involved in other neuromuscular and neurodegenerative disorders. Nevertheless, interpretation of variants in known and potential novel disease genes has remained challenging.     

Deconstructing Fahr's disease/syndrome of brain calcification in the era of new genes

IntroductionThere are now a number genes, known to be associated with familial primary brain calcification (PFBC), causing the so called ‘Fahr's’ disease or syndrome. These are SCL20A2, PDGFB, PDGFRB and XPR1. In this systematic review, we analyse the clinical and radiological features reported in genetically confirmed cases with PFBC. We have additionally reviewed pseudohypoparathyroidism which is a close differential diagnosis of PFBC in clinical presentation and is also genetically determined.MethodsWe performed a Medline search, from 1st Jan 2012 through to 7th November 2016, for publications with confirmed mutations of SCL20A2, PDGFB, PDGFRB, and XPR1 and found twenty papers with 137 eligible cases. A second search was done for publications of cases with Pseudohypoparathyroidism or pseudopseudohypoparathyroidism, and found 18 publications with 20 eligible cases.ResultsSLC20A2 was the most common gene involved with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). Statistically significant correlation was found between the presence of parkinsonism with SLC20A2 mutations, headache in PDGFB and generalised tonic-clonic seizures in patients with pseudohypoparathyroidism.ConclusionWe combine statistical analysis and clinical inference to suggest a diagnostic algorithm based on the observations in this study to help with investigation of a patient with neurological features and brain calcification.     

Electroclinical variability of pyridoxine-dependent epilepsy caused by ALDH7A1 gene mutations in four Taiwanese children

BackgroundThe aim of this study was to describe the electroclinical variability of four Taiwanese patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 gene mutations.MethodsDemographic data, case histories, clinical seizure patterns, EEG features, neuroimaging findings, ALDH7A1 gene mutations, treatments, and neurodevelopmental outcomes of the four patients were collected and analyzed.ResultsThe four patients exhibited the first symptom between the ages of 6 days and 11 months. The age of diagnosis was between 2 months and 13 years 8 months. Patient 1 exhibited classical phenotype of PDE, neonatal onset epileptic encephalopathy. Patient 2 showed atypical phenotypes of intractable epilepsy with additional neurological and abdominal symptoms. Patients 3 and 4, who had normal neurodevelopment, had familial epilepsy with fever sensitivity. Patients 2, 3, and 4 had atypical phenotypes and showed seizure exacerbation during febrile infections. EEG features of patient 1 revealed alternating rhythmic discharges followed by electrodecremental episodes; while those of patients 2, 3, and 4 disclosed nonspecific findings or normal results. Administration of oral pyridoxine hydrochloride resulted in seizure cessation in patients 1, 3, and 4, and they achieved normal neurodevelopmental outcomes, but intractable epilepsy and profound mental retardation occurred in patient 2 as he was not diagnosed until he was 13 years and 8 months old.ConclusionElectroclinical features of PDE vary widely, including patients with normal neurodevelopment and normal or nonspecific EEG findings. To avoid delay in treatment, a therapeutic trial with pyridoxine hydrochloride should be performed in all cases of neonatal, infantile, and childhood refractory epilepsy until ALDH7A1 gene mutation-related PDE has been excluded. Pyridoxine treatment may show clinical effectiveness even in a relatively late stage, i.e., age older than one year.     

Three novel mutations in 20 patients with hereditary spastic paraparesis

Hereditary spastic paraparesis (HSP) constitutes both genetic and clinically heterogeneous group of upper motor neuron diseases. Half of the individuals with autosomal dominant (AD) HSP have mutations in SPAST, ATL1, and REEP1 genes. This study was conducted to elucidate the genetic etiology of patients with the pure type AD-HSP diagnosis. The patient group consisted of 23 individuals from 6 families in Turkey. In the first step of work, Sanger sequencing (SS) was performed in ATL1, SPAST, and REEP1 genes and the second phase whole-exome sequencing (WES) was performed following SS analysis for the patients with no detected mutations in these genes. The results of this study revealed that in ATL1, 6 patients have previously reported c.776C?>?A mutation and 6 patients have novel c.470 T?>?C mutation. In SPAST, 3 patients have novel c.1072G?>?C mutation and 2 patients have novel c.1099-1G?>?C mutation. WES was performed in three patients, who had no detected mutation in these genes with SS analysis. In this approach, as previously reported c.1859 T?>?C mutation in KIAA0196 was detected, and it was confirmed with the patient’s relatives by SS. In three of patients, no HSP-associated variant could be identified in SS and WES. With this study, the molecular genetic etiology in 20 of 23 (87%) individuals that were included in this study with the utilization of SS and WES was elucidated. Utilization of SS and WES methods have enabled the identification of genetic etiology of HSP further with appropriate genetic counseling that was provided to the patients.     

Usefulness of diagnostic tools in a GLUT1 deficiency syndrome patient with 2 inherited mutations

In some patients with GLUT1 deficiency syndrome (GLUT1-DS), the diagnosis can be difficult to reach. We report a child with 2 inherited mutations suggesting an autosomal recessive transmission of SLC2A1 mutations.MethodsThe child and her parents were explored with erythrocyte 3-O-methyl-d-Glucose uptake, glucose uptake in oocytes expressing GLUT1 with the gene mutations and measure of the expression of GLUT1 at the surface of the circulating red blood cells by flow cytometry (METAglut1™ test).ResultsBoth erythrocyte glucose uptake and glucose uptake in oocyte with the patient’s mutations did not support the diagnosis of a mild GLUT1-DS phenotype with autosomal recessive transmission of SLC2A1 mutations. Instead, GLUT-1 expression at the surface of the erythrocytes appeared to better correlate with the clinical phenotypes in this family.ConclusionThe diagnostic value of these functional/expression tools need to be further studied with a focus on mild phenotype of GLUT1-DS.     

Investigating ABCD1 mutations in a Taiwanese cohort with hereditary spastic paraplegia phenotype

BackgroundAdrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by mutations in the ABCD1 gene. The clinical manifestations of ALD vary widely with some patients presenting with adrenomyeloneuropathy (AMN) that resembles the phenotype of hereditary spastic paraplegia (HSP). The aim of this study is to investigate the frequency, spectrum, and clinical features of ABCD1 mutations in Taiwanese patients with HSP phenotype.MethodsMutational analysis of the ABCD1 gene was performed in 230 unrelated Taiwanese patients with clinically suspected HSP by targeted resequencing. Clinical, electrophysiological, and neuroimaging features of the patients carrying an ABCD1 pathogenic mutation were characterized.ResultsTen different ABCD1 mutations were identified in eleven patients, including two novel mutations (p.Q177Pfs*17 and p.Y357*) and eight ever reported in ALD cases of other ethnicities. All patients were male and exhibited slowly progressive spastic paraparesis with onset ages ranging from 21 to 50 years. Most of them had additional non-motor symptoms, including autonomic dysfunction in nine patients, sensory deficits in seven, premature baldness in seven, skin hyperpigmentation in five, psychiatric symptoms in one and cerebellar ataxia in one. Seven of the ten patients who ever received nerve conduction studies showed axonal polyneuropathy. Magnetic resonance imaging (MRI) revealed diffuse spinal cord atrophy in seven patients, cerebral white matter hyperintensity in one patient, and cerebellar involvement in one patient.ConclusionsABCD1 mutations account for 4.8% (11/230) of the cases with HSP phenotype in Taiwan. This study highlights the importance to consider ABCD1 mutations in patients with clinically suspected HSP of unknown genetic causes.     

Clinical utility of genetic testing in pediatric drug-resistant epilepsy: A pilot study

RationaleThe utility of genetic testing in pediatric drug-resistant epilepsy (PDRE), its yield in “real life” clinical practice, and the practical implications of such testing are yet to be determined.GoalTo start to address the above gaps in our knowledge as they apply to a patient population seen in a tertiary care center.MethodsWe retrospectively reviewed our experience with the use of clinically available genetic tests in the diagnosis and management of PDRE in one clinic over one year. Genetic testing included, depending on clinical judgment, one or more of the following: karyotype, chromosomal microarray, single gene sequencing, gene sequencing panels, and/or whole exome sequencing (WES).ResultsWe were more likely to perform genetic testing in patients with developmental delay, epileptic encephalopathy, and generalized epilepsy. In our unique population, the yield of specific genetic diagnosis was relatively high: karyotype 14.3%, microarray 16.7%, targeted single gene sequencing 15.4%, gene panels 46.2%, and WES 16.7%. Overall yield of diagnosis from at least one of the above tests was 34.5%. Disease-causing mutations that were not clinically suspected based on the patients' phenotypes and representing novel phenotypes were found in 6.9% (2/29), with an additional 17.2% (5/29) demonstrating pharmacologic variants. Three patients were incidentally found to be carriers of recessive neurologic diseases (10.3%). Variants of unknown significance (VUSs) were identified in 34.5% (10/29).ConclusionsWe conclude that genetic testing had at least some utility in our patient population of PDRE, that future similar larger studies in various populations are warranted, and that clinics offering such tests must be prepared to address the complicated questions raised by the results of such testing.