Variable Phenotypic Expression Research Articles

Hepatic mitochondrial function in Hereford steers with divergent residual feed intake phenotypes1

Variations in phenotypic expression of feed efficiency could be associated with differences or inefficiencies in mitochondria function due to its impact on energy expenditure. The aim of this study was to determine hepatic mitochondrial density and function in terms of respiration, gene and protein expression, and enzyme activity of mitochondrial respiratory complex proteins, in steers of divergent residual feed intake (RFI) phenotypes. Hereford steers (n = 111 and n = 122 for year 1 and 2, respectively) were evaluated in postweaning 70 d standard test for RFI. Forty-six steers exhibiting the greatest (n = 9 and 16 for year 1 and 2; high-RFI) and the lowest (n = 9 and 12 for year 1 and 2; low-RFI) RFI values were selected for this study. After the test, steers were managed together until slaughter under grazing conditions until they reached the slaughter body weight. At slaughter, hepatic samples (biopsies) were obtained. Tissue respiration was evaluated using high-resolution respirometry methods. Data were analyzed using a mixed model that included RFI group as fixed effect and slaughter date and year as a random effect using PROC MIXED of SAS. RFI and dry matter intake were different (P < 0.001) between low and high-RFI groups of year 1 and year 2. Basal respiration and maximum respiratory rate were greater (P ≤ 0.04) for low than high-RFI steers when complex II substrates (succinate) were supplied. However, when Complex I substrates (glutamate/malate) were used maximum respiratory capacity tended to be greater (P < 0.09) for low vs. high-RFI steers. Low-RFI steers presented greater mitochondria density markers (greater (P < 0.05) citrate synthase (CS) activity and tended (P ≤ 0.08) to have greater CS mRNA and mtDNA:nDNA ratio) than high-RFI steers. Hepatic expression SDHA, UQCRC1, and CYC1 mRNA was greater (P ≤ 0.02) and expression of NDUFA4, NDUFA13, SDHD, UQCRH, and ATP5E mRNA tended (P ≤ 0.10) to be greater in low than high-RFI steers. Hepatic SDHA protein expression tended (P < 0.08) to be greater while succinate dehydrogenase activity was greater (P = 0.04) and NADH dehydrogenase activity was greater (P = 0.03) for low than high-RFI steers. High-efficiency steers (low-RFI) probably had greater efficiency in hepatic nutrient metabolism, which was strongly associated with greater hepatic mitochondrial density and functioning, mainly of mitochondrial complex II.

Gliosarcoma in a young patient with neurofibromatosis type 1. Case report

Introducción. La neurofibromatosis tipo 1 (NF1) es una condición autosómica dominante que presenta una expresividad fenotípica variable, con manifestaciones que van desde lesiones cutáneas hasta compromiso funcional. Se manifiesta clínicamente durante la infancia y la adolescencia; su gen codifica una proteína, la neurofibromina, que actúa como un supresor tumoral en condiciones normales regulando, a su vez, otra proteína que estimula el crecimiento y proliferación celular. En caso de alteración se podrían presentar diferentes procesos tumorales como el que se evidencia en un reducido número de casos. Presentación de caso. Paciente masculino de 20 años con NF1, quien presentaba lesiones cutáneas como manchas color café con leche y desarrolló un glioblastoma, lo cual sucede de manera infrecuente. Discusión. Para obtener el diagnóstico confirmado se incluyen métodos de inmunohistoquímica que contribuyen en gran medida al pronóstico puesto que la mediana de supervivencia global de los pacientes de glioblastoma es mayor en pacientes con NF1 que aquellos sin dicha entidad patológica. Conclusión. El diagnóstico temprano de las lesiones favorece un manejo a tiempo de la NF1. Estos pacientes requieren un manejo integral e interdisciplinar para favorecer su rehabilitación total.

MiRNA Profiling of Magnetic Nanopore-Isolated Extracellular Vesicles for the Diagnosis of Pancreatic Cancer.

Improved diagnostics for pancreatic ductal adenocarcinoma (PDAC) to detect the disease at earlier, curative stages and to guide treatments is crucial to progress against this disease. The development of a liquid biopsy for PDAC has proven challenging due to the sparsity and variable phenotypic expression of circulating biomarkers. Here we report methods we developed for isolating specific subsets of extracellular vesicles (EV) from plasma using a novel magnetic nanopore capture technique. In addition, we present a workflow for identifying EV miRNA biomarkers using RNA sequencing and machine-learning algorithms, which we used in combination to classify distinct cancer states. Applying this approach to a mouse model of PDAC, we identified a biomarker panel of 11 EV miRNAs that could distinguish mice with PDAC from either healthy mice or those with precancerous lesions in a training set of n = 27 mice and a user-blinded validation set of n = 57 mice (88% accuracy in a three-way classification). These results provide strong proof-of-concept support for the feasibility of using EV miRNA profiling and machine learning for liquid biopsy.Significance: These findings present a panel of extracellular vesicle miRNA blood-based biomarkers that can detect pancreatic cancer at a precancerous stage in a transgenic mouse model. Cancer Res; 78(13); 3688-97. ©2018 AACR.

Atypical language characteristics and trajectories in children with 22q11.2 deletion syndrome

Background22q11.2 deletion syndrome (22q11.2DS) is a genetic condition associated with a highly variable phenotypic expression. During childhood speech and language deficits are commonly observed. Findings of cross-sectional studies suggest syndrome-specific and changing language profiles, but a longitudinal approach to identify developmental changes is still lacking to date. AimsThe present study aimed to delineate language characteristics and trajectories by comparing the performance of Dutch-speaking school-aged children with 22q11.2DS (n = 18) to those of peers with idiopathic intellectual disability (IID, n = 19) and to those of children with IID and comorbid autism spectrum disorder (IID + ASD, n = 23). The literature shows contradictory findings regarding language comprehension difficulties in children with 22q11.2DS, we focused on the receptive-expressive language discrepancy. Given their relative strength for verbal short-term memory (VSTM) tasks, a fine-grained error categorization was included to elucidate a possible influence of VSTM on the expressive language outcomes. Finally, we suggested that the inability of children with 22q11.2DS to use contextual information could interfere with morphosyntactic measures. MethodsAll groups (22q11.2DS, IID, and IID + ASD) were matched for nonverbal fluid reasoning (Gf) using the Analogies and Categories subtests of the Snijders-Oomen Nonverbal Intelligence Test or the Matrix Reasoning and Picture Concepts subtests of the Wechsler Preschool and Primary Scale of Intelligence. Several structural language skills were measured using the Clinical Evaluation of Language Fundamentals and Peabody Picture Vocabulary Test. The same instruments were re-administered after 18 to 24 months. A fine-grained error analysis of the Formulating and Recalling Sentences subtests, both measuring expressive syntax, explored factors contributing to expressive language deficits. ResultsIn children with 22q11.2DS the relative advantage of receptive over expressive language had decreased compared to children with IID. For children with 22q11.2DS, complex sentence comprehension remained very challenging over time. Expressive language skills seemed less limited compared to children with IID, and were accompanied by less VSTM difficulties. In children with 22q11.2DS and children with IID + ASD, variable patterns of strengths and weaknesses were demonstrated, resulting in subtle differences between these groups. Error analyses indicated disregard of content-contextual cues and use of vague and elliptic language as being typical for children with 22q11.2DS. ConclusionsWe recommend that in children with 22q11.2DS the impact of the receptive language impairment should be comprehensively examined and followed-up since it can have a negative effect on their social communication skills, adaptive functioning and academic achievement. Error analysis underscores that multiple measures should be used to evaluate the child’s expressive language ability. Further research should focus on developmental trajectories of social communication skills and on the use of intervention strategies to improve language comprehension and pragmatics in school-aged children with 22q11.2DS.

P.020 Novel GRIN2A variant in family members with variable phenotypic expression of epilepsy

Background: Epilepsy aphasia spectrum of disorders is characterized by developmental and language regression with EEG abnormalities that include electrical status epilepticus of sleep (ESES). Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike-wave during sleep (CSWS) are the most severe presentations. GRIN2A mutations have been recognized as causative. Methods: we present two sisters with different epilepsy phenotypes. A variant of unknown clinical significance (VUS) in GRIN2A gene was found in one of the sisters and her similarly affected father. Results: The first sister presented with focal onset seizures at the age of 3 years accompanied by language and cognitive regression and EEG features consistent of ESES, meeting criteria for LKS. Multiple anticonvulsants were tried until she responded well to steroids regaining developmental milestones. Her 5-year-old sister recently presented with focal onset seizures. Her language development is appropriate. Her EEG showed independent multifocal spikes but no ESES during sleep. Her seizures were controlled on monotherapy anticonvulsants. Conclusions: We observed a variable EEG-clinical phenotype and different severity among these family members as expected with GRIN2A-related disorders. This report contributes to evidence of the GRIN2A variant pathogenicity.

Variable Phenotype Expression of a Maternally Inherited 16P13.11 Deletion in Twin Brothers with Epilepsy

Variable Phenotype Expression of a Maternally Inherited 16P13.11 Deletion in Twin Brothers with Epilepsy

Phenotype-Genotype Correlation in Children with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an incidence of ∼1 in 4,000 live births. Neurofibromin, the gene product, is ubiquitously expressed at high levels in the nervous system and functions as a tumor suppressor. Haploinsufficiency of neurofibromin through mutation leads to an increased risk of developing benign and malignant tumors in affected individuals. Although NF1 has complete penetrance, it displays considerable inter- and intrafamilial variability in phenotypic expression which poses disease prediction and management problems. Some NF1 genotype-phenotype correlations have been described. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 52 NF1 patients from 45 families.

Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities.

Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome-related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability.

Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype

<strong>Background:</strong> Spinocerebellar ataxia (SCA) is an uncommon form of progressive cerebellar ataxia with multiple genetic causes and marked variability in phenotypic expression even across patients with identical genetic abnormalities. SCA27 is a recently identified SCA caused by mutations in the Fibroblast Growth Factor 14 gene, with a phenotypic expression that is only beginning to be fully appreciated. We report here a case of a 70-year-old male who presented with slowly worsening tremor and gait instability that began in his early adulthood along with additional features of parkinsonism on examination. Work-up revealed a novel pathogenic mutation in the Fibroblast Growth Factor 14 gene, and symptoms improved with amantadine and levodopa. We also provide a review of the literature in order to better characterize the phenotypic expression of this uncommon condition. <strong>Methods:</strong> Case report and review of the literature. <strong>Results:</strong> Review of the literature revealed a total of 32 previously reported clinical cases of SCA27. Including our case, we found that early-onset tremor (12.1 ± 10.5 years) was present in 95.8%, while gait ataxia tended to present later in life (23.7 ± 16.7 years) and was accompanied by limb ataxia, dysarthria, and nystagmus. Other features of SCA27 that may distinguish it from other SCAs include the potential for episodic ataxia, accompanying psychiatric symptoms, and cognitive impairment. <strong>Discussion:</strong> Testing for SCA27 should be considered in individuals with ataxia who report tremor as an initial or early symptom, as well as those with additional findings of episodic ataxia, neuropsychiatric symptoms, or parkinsonism.

Pla2g6 Deficiency in Zebrafish Leads to Dopaminergic Cell Death, Axonal Degeneration, Increased β-Synuclein Expression, and Defects in Brain Functions and Pathways.

This study aimed to gain insights into the pathophysiology underlying PLA2G6-associated neurodegeneration that is implicated in three different neurological disorders, suggesting that other, unknown genetic or environmental factors might contribute to its wide phenotypic expression. To accomplish this, we downregulated the function of pla2g6 in the zebrafish nervous system, performed parkinsonism-related phenotypic characterization, and determined the effects of gene regulation upon the loss of pla2g6 function by using RNA sequencing and downstream analyses. Pla2g6 deficiency resulted in axonal degeneration, dopaminergic and motor neuron cell loss, and increased β-synuclein expression. We also observed that many of the identified, differentially expressed genes were implicated in other brain disorders, which might explain the variable phenotypic expression of pla2g6-associated disease, and found that top enriched canonical pathways included those already known or suggested to play a major role in the pathogenesis of Parkinson's disease. Our data support that pla2g6 is relevant for cranial motor development with significant implications in the pathophysiology underlying Parkinson's disease.

Same MSH2 Gene Mutation But Variable Phenotypes in 2 Families With Lynch Syndrome: Two Case Reports and Review of Genotype-Phenotype Correlation.

Lynch syndrome is an autosomal dominant syndrome that can be subdivided into Lynch syndrome I, or site-specific colonic cancer, and Lynch syndrome II, or extracolonic cancers, particularly carcinomas of the stomach, endometrium, biliary and pancreatic systems, and urinary tract. Lynch syndrome is associated with point mutations and large rearrangements in DNA MisMatch Repair (MMR) genes. This syndrome shows a variable phenotypic expression in people who carry pathogenetic mutations. So far, a correlation in genotype-phenotype has not been definitely established. In this study, we describe 2 Lynch syndrome cases presenting with the same genotype but different phenotypes and discuss possible reasons for this.

Influence of Apolipoprotein E polymorphism on susceptibility of Wilson disease.

Wilson disease (WD) is an autosomal-recessive disorder caused by mutations in the ATP7B gene leading to abnormal copper deposition in liver and brain. WD manifests diverse neurological and hepatic phenotypes and different age of onset, even among the siblings, with same mutational background suggesting complex nature of the disease and involvement of other candidate genes. In that context, Apolipoprotein E (APOE) and Prion Protein (PRNP) have been proposed to be potential candidates for modifying the WD phenotype and age of onset. This study aims to identify the contribution of APOE and PRNP polymorphisms on the variable phenotypic expression of Indian WD patients. A total of 171 WD patients and 291 controls from Indian population were included in this study. Two APOE cSNPs (rs429358 and rs7412) resulting in three isoforms and M129V (rs1799990) polymorphism of PRNP were examined for their association with WD and its clinical phenotypes. The APOE ԑ4 allele was found to be significantly overrepresented in WD patients compared to controls. However, the frequency of the APOE ԑ3 allele and ԑ3/ԑ3 genotype was significantly higher in WD patients without cognitive behavior impairment compared to the ones with the impairment. On the contrary, the PRNP allele representing Val129 was found to be present in higher proportion in WD patients with cognitive behavioral decline. Our data suggest that the APOE ԑ4 allele could act as a potential risk for the pathogenesis of WD. Also, APOE and PRNP might contribute toward the cognitive behavioral decline in a section of WD patients.

The 22q11.2 deletion syndrome: Cancer predisposition, platelet abnormalities and cytopenias.

The 22q11.2 deletion syndrome (DS) is associated with variable phenotypic expression as findings range from severely affected individuals with the classical triad of DiGeorge and velocardiofacial syndromes, including congenital heart disease, immunodeficiency, hypocalcemia, and palatal abnormalities, to subtly affected adults who only come to attention following the diagnosis of a more severely affected child. The multiple manifestations can affect all organ systems, including the hematologic system resulting in baseline lower platelet counts for individuals with 22q11.2DS and increased platelet size. In addition, there may be an associated increased risk of bleeding. Individuals with 22q11.2DS are also at increased risk of autoimmune cytopenias that can complicate the evaluation or management of other manifestations. Finally, there may be an increased risk of malignancy, although the mechanism for this risk is not fully understood. This review summarizes the currently available data on hematologic/oncologic manifestations of 22q11.2DS and reports on our findings within a large cohort of individuals with the deletion.

Variable phenotypic expression in a large Noonan syndrome family segregating a novel SOS1 mutation.

Noonan syndrome (NS) is an autosomal dominant multisystem condition with a variable phenotype. The most characteristic features are short stature, congenital heart defects, and recognizable facial features. Mutations in SOS1 are found in 10-20% of patients with NS. Different genotype-phenotype studies mention correlations between SOS1 mutations and some features, such as ectodermal abnormalities and specific facial features. We present a large NS family with a novel pathogenic mutation; SOS1 c.3134C>G, p.Pro1045Arg. Ten family members with NS are included with genetically confirmed mutation and clinical evaluation. The phenotype shows a broad spectrum from only few suggestive features for NS in the older generation to typical features in the youngest generation. We report on a novel pathogenic mutation in the SOS1 gene and a large clinical spectrum in a NS family with ten genetically confirmed affected individuals.

Generalized paroxysmal fast activity in EEG: An unrecognized finding in genetic generalized epilepsy

ObjectiveTo study generalized paroxysmal fast activity (GPFA) in patients with genetic generalized epilepsy (GGE). IntroductionGPFA is an electroencephalographic (EEG) finding in patients with symptomatic generalized epilepsy consisting of 15-25Hz bifrontally predominant generalized fast activity seen predominantly in sleep. Historically GPFA is linked to epileptic encephalopathy with drug resistant epilepsy and intellectual disability. However, GPFA has been rarely described as an atypical finding in patients with GGE without negative prognostic implication. We report cognitive profile and seizure characteristics in seven patients with GGE and GPFA. MethodsThe Vanderbilt EMU and EEG reports were searched for the keywords “idiopathic generalized epilepsy”, “GPFA”and “generalized spike and wave discharges (GSWD)”. We reviewed the EEG tracings and the electronic medical records of patients thus identified. The seizure type, frequency, neurological work-up, clinical profile and imaging data were recorded. ResultsAwake and sleep states were captured on EEGs of all patients. On EEG tracing review six patients were confirmed to have GSWD and GPFA; one patient had GPFA but no GSWD. All patients had normal cognitive function. Four had a normal brain MRI and one a normal head CT (two were never imaged). None of the patients had tonic seizures. The main seizure type was generalized tonic-clonic seizures (GTCS) in five patients, absence in two. Age at onset of epilepsy ranged from 4 to 24years. The mean GTC seizure frequency at the time of EEG was 3; two patients were seizure free on two antiepileptic drugs (AEDs). ConclusionsGPFA can be an unrecognized electrographic finding in patients with genetic generalized epilepsy. While GPFA remains an important diagnostic EEG feature for epileptic encephalopathy (Lennox-Gastaut syndrome) it is not specific for this diagnosis. Thus, GPFA may have a spectrum of variable phenotypic expression. The finding of GPFA is not necessarily indicative of unfavorable outcome.

Panel-based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns.

BackgroundMicrophthalmia and anophthalmia (MA) are congenital eye abnormalities that show an extremely high clinical and genetic complexity. In this study, we evaluated the implementation of whole exome sequencing (WES) for the genetic analysis of MA patients. This approach was used to investigate three unrelated families in which previous single‐gene analyses failed to identify the molecular cause.MethodsA total of 47 genes previously associated with nonsyndromic MA were included in our panel. WES was performed in one affected patient from each family using the AmpliSeqTM Exome technology and the Ion ProtonTM platform.ResultsA novel heterozygous OTX2 missense mutation was identified in a patient showing bilateral anophthalmia who inherited the variant from a parent who was a carrier, but showed no sign of the condition. We also describe a new PAX6 missense variant in an autosomal‐dominant pedigree affected by mild bilateral microphthalmia showing high intrafamiliar variability, with germline mosaicism determined to be the most plausible molecular cause of the disease. Finally, a heterozygous missense mutation in RBP4 was found to be responsible in an isolated case of bilateral complex microphthalmia.ConclusionThis study highlights that panel‐based WES is a reliable and effective strategy for the genetic diagnosis of MA. Furthermore, using this technique, the mutational spectrum of these diseases was broadened, with novel variants identified in each of the OTX2,PAX6, and RBP4 genes. Moreover, we report new cases of reduced penetrance, mosaicism, and variable phenotypic expressivity associated with MA, further demonstrating the heterogeneity of such disorders.

A novel mutation in SMOC1 and variable phenotypic expression in two patients with Waardenburg anophthalmia syndrome

Waardenburg anophthalmia syndrome (WAS) is a rare disorder that mostly affects the eyes and distal limbs. In the current study we reported two Iranian patients with WAS.The first case was a 26-year-old girl with unilateral anophthalmia, bilateral camptodactyly and clinodactyly in her hands, oligodactly in her left foot and syndactyly of the second to fifth toes in her right foot. She also had severe hearing loss in both ears. The second case was a 12-year-old boy with bilateral anophthalmia, camptodactyly in his right hand, oligodactyly in his foot, clubfoot, and cryptorchidism. Both patients were mentally normal. To detect the causative mutation all exons and exon-intron boundaries of SMOC1 gene were sequenced in patients and other normal family members. We found a homozygous missense mutation (NM_001034852.2(SMOC1):c.367T > C) in exon 3 of SMOC1 gene in both patients. As the mutation segregated with the disease in the family, it should be the causative mutation. Our study extended the mutation spectrum of SMOC1 gene related to WAS.

A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation

BackgroundVariable expressivity is a well-known phenomenon in which patients with mutations in one gene display varying degrees of clinical severity, potentially displaying only subsets of the clinical manifestations associated with the multisystem disorder linked to the gene. This remains an incompletely understood phenomenon with proposed mechanisms ranging from allele-specific to stochastic.ResultsWe report three consanguineous families in which an isolated ocular phenotype is linked to a novel 3′ UTR mutation in SLC4A4, a gene known to be mutated in a syndromic form of intellectual disability with renal and ocular involvement. Although SLC4A4 is normally devoid of AU-rich elements (AREs), a 3′ UTR motif that mediates post-transcriptional control of a subset of genes, the mutation we describe creates a functional ARE. We observe a marked reduction in the transcript level of SLC4A4 in patient cells. Experimental confirmation of the ARE-creating mutation is shown using a post-transcriptional reporter system that reveals consistent reduction in the mRNA-half life and reporter activity. Moreover, the neo-ARE binds and responds to the zinc finger protein ZFP36/TTP, an ARE-mRNA decay-promoting protein.ConclusionsThis novel mutational mechanism for a Mendelian disease expands the potential mechanisms that underlie variable phenotypic expressivity in humans to also include 3′ UTR mutations with tissue-specific pathology.

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes

Autism spectrum disorder is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 genomic loci are deemed to be associated with susceptibility to autism spectrum disorder, showing de novo and inherited unbalanced copy number variants and smaller insertions and deletions (indels), more complex structural variants, as well as single-nucleotide variants deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two copy number variant microdeletions, which affect regions of NRXN1 and MBD5—each well-established in association with risk of autism spectrum disorder and other neurodevelopmental disorders. Although each copy number variant would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks.