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TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3’s direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease.

OBJECTIVE: To refine the natural history and genotype-phenotype correlations of OTOF-related auditory neuropathy spectrum disorders (ANSD) through the analysis of audiograms and distortion product otoacoustic emissions (DPOAEs) in a diverse cohort of individuals with hearing loss. METHODS: Audiograms and DPOAEs were collected from individuals diagnosed with OTOF-related ANSD by comprehensive genetic testing and from the published literature. Comparative analysis was undertaken to determine genotype-phenotype relationships using a Monte Carlo algorithm. RESULTS: 67 audiograms and 25 DPOAEs from 49 unique individuals positive for OTOF-related ANSD were collected. 51 unique OTOF pathogenic variants were identified of which 21 were missense and 30 were loss of function (LoF; nonsense, splice-site, copy number variants, and indels). There was a statistically significant difference in low, middle, and high frequency pure tone average hearing loss thresholds with missense/missense and LoF/missense genotypes (average: 70.9, 76.0, and 73.4 dB hearing loss) compared with LoF/LoF genotypes (average: 88.5, 95.6, and 94.7 dB hearing loss) via Tukey’s test with age as a co-variate (P = 0.0180, 0.0327, and 0.0347 respectively). Hearing declined during adolescence with missense/missense and LoF/missense genotypes with an annual mid-frequency threshold deterioration of 0.87 dB/year and 1.87 dB/year, respectively. 8.5% of measured frequencies via DPOAE were lost per year in individuals with serial tests. CONCLUSIONS: Audioprofiling of OTOF-related ANSD suggests significantly worse hearing with LoF/LoF genotypes. OTOF-related ANSD causes a unique pattern of variably progressive autosomal recessive auditory neuropathy that may be amenable to gene therapy in selected clinical scenarios.

Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders with a strong heritable genetic component. At present, ASD is diagnosed solely by behavioral criteria. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD, where rare mutations and s common variants contribute to its susceptibility. Moreover, studies show rare de novo variants, copy number variation and single nucleotide polymorphisms (SNPs) also impact neurodevelopment signaling. Exploration of rare and common variants involved in common dysregulated pathways can provide new diagnostic and therapeutic strategies for ASD. Contributions of current innovative molecular strategies to understand etiology of ASD will be explored which are focused on whole exome sequencing (WES), whole genome sequencing (WGS), microRNA, long non-coding RNAs and CRISPR/Cas9 models. Some promising areas of pharmacogenomic and endophenotype directed therapies as novel personalized treatment and prevention will be discussed.

Pharmacogenomics (PGx) is a growing field within precision medicine. Testing can help predict adverse events and sub-therapeutic response risks of certain medications. To date, the US FDA lists over 280 drugs which provide biomarker-based dosing guidance for adults and children. At Arkansas Children’s Hospital (ACH), a clinical PGx laboratory-based test was developed and implemented to provide guidance on 66 pediatric medications for genotype-guided dosing. This PGx test consists of 174 single nucleotide polymorphisms (SNPs) targeting 23 clinically actionable PGx genes or gene variants. Individual genotypes are processed to provide per-gene discrete results in star-allele and phenotype format. These results are then integrated into EPIC- EHR. Genomic indicators built into EPIC-EHR provide the source for clinical decision support (CDS) for clinicians, providing genotype-guided dosing.

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

Clinical genetics has evolved significantly to become an efficient and effective means of diagnosing disease. Genetic treatments are now being developed which are showing promising results. However, ophthalmic patients are not utilizing genetic testing as part of their diagnostic workups. This paper explores the patient experience at the Ocular Genetics Clinic (OGC) at the University of Arkansas for Medical Sciences (UAMS) Jones Eye Institute and discusses reasons why patients continue to not pursue genetic testing.We performed a retrospective chart review to understand the main reasons why patients were referred to the OGC between 2009 and 2018, with a detailed analysis of why patients did not pursue genetic testing.Patients mainly did not undergo testing due to the cost of testing. However, patient availability, patient interest, and diagnostic workup also drove a significant amount of this lack of testing.Ocular genetic testing is becoming an increasingly beneficial tool for diagnosing ocular disease. However, to date, patients do not utilize this service fully. At the OGC, there are several main drivers for this lack of testing, namely finances, interest/availability, and diagnostic workup. As more ocular genetics clinics are established, it will be imperative to address reasons for forgoing genetic testing and to develop strategies to encourage patients to pursue this testing.

Purpose: This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. Methods: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. Results: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. Conclusion: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care. ispartof: GENETICS IN MEDICINE vol:21 issue:4 pages:867-876 ispartof: location:United States status: published

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b(−/−) mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b(−/−) cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b(−/−) mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b(−/−) mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.

The RNA polymerase II complex (pol II) is responsible for transcription of all similar to 21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

We explored the clinico-genetic basis of spinocerebellar ataxia 29 (SCA29) by determining the frequency, phenotype, and functional impact of ITPR1 missense variants associated with early-onset ataxia (EOA). Three hundred thirty one patients from a European EOA target cohort (n = 120), US-American EOA validation cohort (n = 72), and early-onset epileptic encephalopathy (EOEE) control cohort (n = 139) were screened for de novo ITPR1 variants. The target cohort was also screened for inherited ITPR1 variants. The variants' functional impact was determined by IP3-induced Ca2+ release in HEK293 cells. 3/120 patients (2.5%) from the target cohort and 4/72 patients (5.5%) from the validation cohort, but none from the EOEE control cohort, carried de novo ITPR1 variants. However, most ITPR1 variants (7/10 = 70%) in the target cohort were inherited from a healthy parent, with 3/6 patients carrying disease-causing variants in other genes. This suggests limited or no phenotypic impact of many ITPR1 missense variants, even if ultra-rare and well-conserved. While common bioinformatics tools did not discriminate de novo from other ITPR1 variants, functional characterization demonstrated reduced IP3-induced Ca2+ release for all de novo variants, including the recurrent c.805C>T (p.(R269W)) variant. In sum, these findings show that de novo ITPR1 missense variants are a recurrent cause of EOA (SCA29) across independent cohorts, acting via loss of IP3 channel function. Inherited ITPR1 variants are also enriched in EOA, but often without strong impact, albeit rare and well-conserved. Functional studies allow identifying ITPR1 variants with large impact, likely disease-causing. Such functional confirmation is warranted for inherited ITPR1 variants before making a SCA29 diagnosis.

Congenital anomalies or birth defects account for one of the leading causes of death in infants. When one anomaly is present, there is a 50% risk that other anomalies are present. Healthcare providers taking care of newborns should have a low threshold to look for additional anomalies in the presence of one. These anomalies may not always be identified in the hospital but may require evaluation after discharge. Close attention to the type and pattern of anomalies also provides clues to the underlying diagnosis. Genetic consultation is critical to help identify patterns and guide appropriate testing, especially in this time of ever-changing and complex diagnostic options.

Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality.

PIGT-CDG, an autosomal recessive syndromic intellectual disability disorder of glycosylphosphatidylinositol (GPI) anchors, was recently described in two independent kindreds [Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (OMIM, #615398)]. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of the heteropentameric transamidase complex that facilitates the transfer of GPI to proteins. GPI facilitates attachment (anchoring) of proteins to cell membranes. We describe, at ages 7 and 6years, two children of non-consanguineous parents; they had hypotonia, severe global developmental delay, and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Exome sequencing revealed that both siblings had compound heterozygous variants in PIGT (NM_015937.5), i.e., c.918dupC, a novel duplication leading to a frameshift, and c.1342C>T encoding a previously described missense variant. Flow cytometry studies showed decreased surface expression of GPI-anchored proteins on granulocytes, consistent with findings in previous cases. These siblings further delineate the clinical spectrum of PIGT-CDG, reemphasize the neuro-ophthalmologic presentation, clarify the endocrine features, and add hypermobility, low CSF albumin quotient, and hearing loss to the phenotypic spectrum. Our results emphasize that GPI anchor-related congenital disorders of glycosylation (CDGs) should be considered in subjects with early onset severe seizure disorders and dysmorphic facial features, even in the presence of a normal carbohydrate-deficient transferrin pattern and N-glycan profiling. Currently available screening for CDGs will not reliably detect this family of disorders, and our case reaffirms that the use of flow cytometry and genetic testing is essential for diagnosis in this group of disorders.

Purpose This study described the perceptions of genetic counseling and testing of adults ( N =116) attending a genetic education program. Understanding perceptions of genetic counseling, including the importance of counseling topics, will contribute to patient-focused care as clinical genetic applications for common, complex disorders evolve. Methods Participants completed a survey addressing: the importance of genetic counseling topics, benefits and negative effects of genetic testing, and sharing test results. Results Topics addressing practical information about genetic conditions were rated most important; topics involving conceptual genetic/genomic principles were rated least important. The most frequently identified benefit and negative effect of testing were prevention/early detection/treatment and psychological distress. Participants perceived that they were more likely to share test results with first-degree than other relatives. Conclusions Findings suggest providing patients with practical information about genetic testing and genetic contributions to disease, while also determining whether their self-care abilities would be enhanced by teaching genetic/genomic principles.

Sex chromosome aneuploidies range in incidence from rather common to exceedingly rare and have a variable phenotype. We report 2 patients with sex chromosome aneuploidies who developed severe aplastic anemia requiring treatment. The first patient had tetrasomy X (48,XXXX) and presented at 9 years of age, and the second patient had trisomy X (47,XXX) and presented at 5 years of age. Although aplastic anemia has been associated with other chromosomal abnormalities, sex chromosome abnormalities have not been traditionally considered a risk factor for this condition. A review of the literature reveals that at least one other patient with a sex chromosome aneuploidy (45,X) has suffered from aplastic anemia and that other autosomal chromosomal anomalies have been described. Despite the uncommon nature of each condition, it is possible that the apparent association is coincidental. A better understanding of the genetic causes of aplastic anemia remains important.

Key Clinical Message Rubinstein–Taybi syndrome is associated with intellectual and physical features. CREBBP and EP300 are causative. Few cases of EP300 mutations are reported. We report a case with mild features of RSTS and EP300 mutation on exome sequencing. This illustrates the utility of exome sequencing to expand every genetic phenotype.

Autosomal recessive bestrophinopathy (ARB) is a retinal disease caused by biallelic mutations of the BEST1 gene. It has a variable phenotype with white flecks in the retina, multifocal yellow subretinal deposits, macular edema, choroidal neovascularization, hyperopia, and electrophysiological abnormalities. We describe a family with ARB and multigenerational inheritance.Three generations of a Middle Eastern family (a woman, one son, and two grandchildren) were evaluated by our ocular genetics team. Eye examinations, fundus photography, and optical coherence tomography (OCT) were performed. Genetic testing was obtained on examined patients and available relatives.The proband demonstrated counting fingers vision and white flecks in the retinal periphery, with macular subretinal fluid (SRF), loss of outer photoreceptor segments, and epiretinal membrane (ERM) on OCT. Two grandchildren demonstrated decreased vision, multifocal yellow subretinal deposits, and SRF on OCT. Two grandchildren examined elsewhere were reported to be similarly affected. A son's examination was normal except for extra-macular scars (from prior toxoplasmosis) and ERM. Genetic history revealed consanguinity and testing showed homozygosity for BEST1 mutations in the proband and two grandchildren c.473GA/c.473GA (R218H /R218H) and heterozygosity in two unaffected sons and two unaffected daughters-in-law c.473GA/WT (p.R218H/WT).We present a consanguineous family of five affected individuals with ARB and four confirmed carriers. Their pedigree was consistent with dominant inheritance and incomplete penetrance. Genetic testing clarified the diagnosis and mode of inheritance. We describe the genetic findings, phenotypic variability, and recessive inheritance of an often dominantly inherited mutation as notable elements in their case.

In the Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes study, 9/20 erythropoietin-treated vs 12/24 placebo-treated infants with hypoxic-ischemic encephalopathy had acute brain injury. Among infants with acute brain injury, the injury volume was lower in the erythropoietin than the placebo group (P = .004). Higher injury volume correlated with lower 12-month neurodevelopmental scores. Trial registration ClinicalTrials.gov : NCT01913340 .

Early brain injury occurs in newborns with congenital heart disease (CHD) placing them at risk for impaired neurodevelopmental outcomes. Predictors for preoperative brain injury have not been well described in CHD newborns. This study aimed to analyze, retrospectively, brain magnetic resonance imaging (MRI) in a heterogeneous group of newborns who had CHD surgery during the first month of life using a detailed qualitative CHD MRI Injury Score, quantitative imaging assessments (regional apparent diffusion coefficient [ADC] values and brain volumes), and clinical characteristics. Seventy-three newborns that had CHD surgery at 8 ± 5 (mean ± standard deviation) days of life and preoperative brain MRI were included; 38 also had postoperative MRI. Thirty-four (34/73, 47%) had at least 1 type of preoperative brain injury, and 28/38 (74%) had postoperative brain injury. The 5-minute APGAR score was negatively associated with preoperative injury, but there was no difference between CHD types. Infants with intraparenchymal hemorrhage, deep gray matter injury, and/or watershed infarcts had the highest CHD MRI Injury Scores. ADC values and brain volumes were not different in infants with different CHD types, or in those with and without brain injury. In a mixed group of CHD newborns, brain injury was found preoperatively on MRI in almost 50%, and there were no significant baseline characteristic differences to predict this early brain injury, except 5-minute APGAR score. We conclude that all infants, regardless of CHD type, who require early surgery, should be evaluated with MRI as they are all at high risk for brain injury.

Human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2) has been previously associated with intellectual disability and developmental delay in three patients. Here, we describe six patients with developmental delay, intellectual disability, and dysmorphic features with de novo likely gene-damaging variants in HIVEP2 identified by whole-exome sequencing (WES). HIVEP2 encodes a large transcription factor that regulates various neurodevelopmental pathways. Our findings provide further evidence that pathogenic variants in HIVEP2 lead to intellectual disabilities and developmental delay.

Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for ~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year-old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered.

We identified five unrelated individuals with significant global developmental delay and intellectual disability (ID), dysmorphic facial features and frequent microcephaly, and de novo predicted loss-of-function variants in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). Our findings are consistent with recently reported de novo mutations in CHAMP1 in five other individuals with similar features. CHAMP1 is a zinc finger protein involved in kinetochore–microtubule attachment and is required for regulating the proper alignment of chromosomes during metaphase in mitosis. Mutations in CHAMP1 may affect cell division and hence brain development and function, resulting in developmental delay and ID.

Early presumptions opined that autism spectrum disorder (ASD) was related to the rearing of these children by emotionally-distant mothers. Advances in the 1960s and 1970s clearly demonstrated the biologic basis of autism with a high heritability. Recent advances have demonstrated that specific etiologic factors in autism spectrum disorders can be identified in 30%-40% of cases. Based on early reports newer, emerging genomic technologies are likely to increase this diagnostic yield to over 50%. To date these investigations have focused on etiologic factors that are largely mono-factorial. The currently undiagnosed causes of ASDs will likely be found to have causes that are more complex. Epigenetic, multiple interacting loci, and four dimensional causes (with timing as a variable) are likely to be associated with the currently unidentifiable cases. Today, the "Why" is more important than ever. Understanding the causes of ASDs help inform families of important issues such as recurrence risk, prognosis, natural history, and predicting associated co-morbid medical conditions. In the current era of emerging efforts in "personalized medicine", identifying an etiology will be critical in identifying endo-phenotypic groups and individual variations that will allow for tailored treatment for persons with ASD.

The primary goal of infant hearing screening is, of course, the improved outcome of speech and language in those identified early. There is, however, another major advantage in the early detection of hearing loss. Hearing loss identified by newborn screening can prompt an early investigation into the etiology of the loss. Most cases of hearing loss detected by newborn screening have a genetic etiology. A genetics evaluation can provide the family and providers with several critical pieces of information. For many families, simply knowing the “why” is an important question. Identifying an etiology can also answer questions about recurrence risks for the immediate and extended family. In addition, many of the causes of childhood hearing loss have associated medical conditions, some of which can be medically serious. Knowledge of these risk factors can lead to interventions that prevent morbidity and mortality. All health care providers who work with children with a hearing loss should be aware of the details of a genetic evaluation. They should be prepared to share with the family information regarding the process, the diagnostic yield, and the risks and benefits of such an evaluation.

Chromosomal band 1q21.1 can be divided into two distinct regions, proximal and distal, based on segmental duplications that mediate recurrent rearrangements. Microdeletions and microduplications of the distal region within 1q21.1, which are susceptibility factors for a variety of neurodevelopmental phenotypes, have been more extensively studied than proximal microdeletions and microduplications. Proximal microdeletions are known as a susceptibility factor for thrombocytopenia-absent radius (TAR) syndrome, but it is unclear if these proximal microdeletions have other phenotypic consequences. Therefore, to elucidate the clinical significance of rearrangements of the proximal 1q21.1 region, we evaluated the phenotypes in patients identified with 1q21.1 rearrangements after referral for clinical microarray testing. We report clinical information for 55 probands with copy number variations (CNVs) involving proximal 1q21.1: 22 microdeletions and 20 reciprocal microduplications limited to proximal 1q21.1 and 13 microdeletions that include both the proximal and distal regions. Six individuals with proximal microdeletions have TAR syndrome. Three individuals with proximal microdeletions and two individuals with larger microdeletions of proximal and distal 1q21.1 have a ‘partial' TAR phenotype. Furthermore, one subject with TAR syndrome has a smaller, atypical deletion, narrowing the critical deletion region for the syndrome. Otherwise, phenotypic features varied among individuals with these microdeletions and microduplications. The recurrent, proximal 1q21.1 microduplications are enriched in our population undergoing genetic testing compared with control populations. Therefore, CNVs in proximal 1q21.1 can be a contributing factor for the development of abnormal phenotypes in some carriers.

A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial- digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria. Hum Mutat 31:1142-1154, 2010. (C) 2010 Wiley-Liss, Inc

Cerebral palsy refers to a collective of neurologic conditions that share in common disorders of motor function and posture. Traditionally, and still today in many circles, the term is considered almost synonymous with brain injury. Multiple lines of evidence, however, point to the fact that cerebral palsy is rarely caused by problems with perinatal management. In fact, a mounting body of evidence points to strong genetic influences on the occurrence of cerebral palsy. Like most neurogenetic conditions, cerebral palsy exhibits complex inheritance. The best descriptor of the inheritance of cerebral palsy would be that of "multifactorial inheritance." This implies etiologic and genetic heterogeneity with complex interactions with multiple environmental influences. This article reviews known genetic influences on the origin of cerebral palsy. A proposed scheme for the genetic evaluation in identifying the etiology of cerebral palsy is provided.

The autism spectrum disorders are a collection of conditions, which have, in common, impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased markedly over the past decade. In addition, a large amount of attention has been paid to these conditions among lay and professional groups. These influences have resulted in a marked increase in the number of referrals to clinical geneticists for evaluation of persons with autism spectrum disorders. The primary role of the geneticist in this process is to define etiology, if possible, and to provide counseling and contribute to case management based on the results of such investigations. In deciding upon the appropriate evaluation scheme for a particular patient, the geneticist must consider a host of different factors. Such considerations would include (1) Assuring an accurate diagnosis of autism before proceeding with any investigation. (2) Discussing testing options, diagnostic yields, and patient investment before proceeding with an evaluation. (3) Communication and coordination with the patient's medical home. (4) Assessing the continuously expanding and evolving list of available laboratory testing modalities in light of evidence-based medicine. (5) Recognizing expanded phenotypes of well-described syndromic and metabolic conditions that encompass autism spectrum disorders. (6) Defining an individualized evaluation scheme based on the unique history and clinical features of a given patient. The guidelines in this article have been developed to assist the clinician in the consideration of these factors.

Objectives: The primary purpose of this study was to describe individuals' knowledge and beliefs about genetics and smoking. Secondary purposes were to describe (a) differences in knowledge and beliefs based on smoking status, gender, and education and (b) relationships among perceived genetic predisposition for smoking, background characteristics, and knowledge and beliefs about genetics and smoking. Because genetics influences smoking, genetic information will likely be used to individualize future cessation treatment. Design: Questionnaire data were collected about knowledge and beliefs about genetics and smoking, smoking history, and demographics from visitors and staff at a nursing care facility. Data were analyzed with bivariate statistics and logistic regression. Sample: Participants (N=92), ages 19–82, were classified by smoking status. Results: Participants had little knowledge about genetics and smoking or mechanisms of heredity. Most did not believe that genetics caused smoking or influenced cessation. Predictors of perceived genetic predisposition for smoking were smoking status (current/former smoker), education (

The coexistence of two or more distinct genetic conditions is known to be a rare phenomenon. Full chromosome aneuploidies can be associated with a broad variety of cytogenetic abnormalities or single gene disorders resulting in phenotypic modifications that confuse the diagnostic process. We present six patients with primary aneuploidies and a suspected or confirmed secondary genetic diagnosis or unusual birth defect. Among the cases included, we report the first patients with concurrent Down syndrome in combination with Prader-Willi, Craniofacial Microsomia, and Stickler syndromes. We also describe only the second reported case of a neonate with Down syndrome and Marfan syndrome. In all cases, the unusual clinical presentations lead to further molecular cytogenetic studies as well as single or multi-gene molecular evaluations. We make emphasis on the importance of entertaining the possibility of coexistent diagnoses when the phenotype is not what is expected for aneuploidies rather than attributing the unusual findings to rare or unreported associations of the primary aneuploidy.

Purpose: Clinical geneticists are often asked to evaluate patients with autism spectrum disorders (ASDs) in reference to questions about cause and recurrence risk. Recent advances in diagnostic testing technology have greatly increased the options available to them. It is not currently clear what the overall diagnostic yield of a battery of tests, either collectively or individually, might be. The purpose of this study was to evaluate the diagnostic yield of a stepwise approach we have implemented in our clinics. Methods: We used a three-tiered neurogenetic evaluation scheme designed to determine the cause of ASDs in patients referred for clinical genetic consultation. We reviewed the results of our diagnostic evaluations on all patients referred with a confirmed diagnosis of autism over a 3-year period. Results: By using this approach, we found an overall diagnostic yield for ASDs of more than 40%. This represents a significant increase in the diagnostic yield reported just a few years ago. Conclusions: Given the implications of these diagnoses on recurrence risk and associated medical conditions, a targeted neurogenetic evaluation of all persons with ASDs seems warranted. We discuss the issues in the future implementation of a fourth tier to the evaluation with the potential for an even higher diagnostic yield.

Mandibulofacial dysostosis with microcephaly is a rare syndromic craniofacial condition caused by heterozygous loss-of-function mutations of the EFTUD2 gene on 17q21.31. Thus far, the described musculoskeletal findings in patients with this condition include proximally placed or duplicated thumbs, overlapping toes, and toe syndactyly. We describe a severe case of a patient with a 17q21.31 microdeletion and many of the phenotypic features described in mandibulofacial dysostosis with microcephaly who had bilateral proximal radioulnar synostosis and brain abnormalities. This provides further evidence of the clinical overlap among mandibulofacial and acrofacial dysostoses syndromes and expands the phenotype of EFTUD2 haploinsufficiency due to larger deletions.

Purpose: Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid α-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder. Methods: The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II. rhGAA used in this study was purified from genetically engineered Chinese hamster ovary (CHO) cells overproducing GAA. Adverse effects and efficacy of rhGAA upon cardiac, pulmonary, neurologic, and motor functions were evaluated during 1 year of the trial period. The primary end point assessed was heart failure–free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age. Results: The results of more than 250 infusions showed that rhGAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants have well passed the critical age of 1 year (currently 16, 18, and 22 months old) and continue to have normal cardiac function. Improvements of skeletal muscle functions were also noted; one patient showed marked improvement and currently has normal muscle tone and strength as well as normal neurologic and Denver developmental evaluations. Muscle biopsies confirmed that dramatic reductions in glycogen accumulation had occurred after rhGAA treatment in this patient. Conclusions: This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.

We present a single case of a young man with multiple congenital anomalies. For years, a unifying diagnosis could not be made. As his case developed, more clues came to light, but still no recognizable pattern could be identified. Ultimately, the combination of orofacial clefting, neurosensory hearing loss, choroideremia, and cognitive delays were shown to be due to an Xq21 [corrected] micro-deletion as seen on comparative genomic hybridizations studies. A review of the genes contained in this region clearly explain his constellation of findings.

Nevus of Ota is a benign congenital melanocytic lesion found most commonly in people of Asian ancestry. It is associated with an increased risk of glaucoma and uveal melanomas. Most cases are sporadic and unilateral. We present the first reported case of a brother and sister with familial, bilateral nevus of Ota.

Congenital hyperinsulinism (CHI) is a rare metabolic disease characterized by inappropriate insulin secretion in the presence of hypoglycemia. We describe the clinical presentation and management of congenital hyperinsulinism and persistent hypoglycemia in two infants. Both patients had an initial clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) but normal methylation analysis for LIT1 and H19 status. Both patients were eventually found to have mosaic uniparental disomy 11p diagnosed by single nucleotide polymorphism (SNP) array in DNA isolated from lymphoblasts and fibroblasts, respectively. We report that patients with mosaic BWS are at increased risk for both transient and refractory hypoglycemia that may need aggressive management with diazoxide, octreotide, high glucose infusion rates, and a frequent feeding regime. Our patient experience supports the case for pursuing further testing in patients with features of BWS with normal methylation studies, karyotype, and SNP arrays on blood. The next logical step is SNP array on skin biopsy to rule out mosaicism.

Advances in technology and telecommunications have opened the door for primary care pediatricians to provide a range of medical services that extend the walls of their medical home. Constraints of time, distance, and access can be overcome with electronic transmission of medical information that provide patients care when and where they need it by providers they know and trust. No longer are on-call pediatricians staying home tied to their land-line telephone, assessing acute conditions based only on parent descriptions and documenting the conversation on paper call slips. If this sounds like you, please read this article for a 2009 alternative.

Attention to a careful diagnostic work-up should be given to patients with postaxial polydactyly or apparently isolated hypothalamic hamartomas. Early recognition of the condition is critical for management, particularly for anticipating and preventing endocrine emergencies. Conservative management of the hypothalamic hamartoma should be stressed. Finally, detailed genetic counseling should be provided to the family regarding autosomal-dominant inheritance as well as the wide range of interfamilial and intrafamilial variability.

The recent progress in matrix metalloproteinases (MMPs) research has opened up many cellular targets in a variety of diseases. We have discussed some of the interesting and newly described roles of MMPs in modulating metastatic phenotype in malignancies. This information suggests a more specific and exclusive role of MMPs as important regulators of tumor cell invasion and metastasis. A great deal of room exists for redefining our current understanding of the MMPs system; the more we understand about how MMPs act, the better we will understand the pathobiology of metastasis. Research in the regulation of MMPs and the potential use of MMPs for therapeutic interventions in metastasis continues to expand. The future of therapy involving inhibitors of MMPs as a part of the armamentarium against human neoplasm should be viewed with cautious optimism. This therapeutic approach is beginning to find a place in our understanding of metastatic tumors, but with perhaps few exceptions should still be considered experimental. This area of research now needs more biological knowledge and imagination on the part of investigators to make future achievements possible.

We report 2 cases of patients with a rare multiple anomaly condition reported as Dellman (oculocerebrocutaneous) syndrome. In this article we discuss the clinical features and genetics of this condition. Notably, both of these patients have digital abnormalities which have not been previously described in the literature.

The cause of Sotos syndrome is unknown but it usually occurs sporadically. Recent studies have shown no evidence of uniparental disomy. One set of concordant monozygotic twins has been reported. We have identified the Sotos syndrome in one of two 5-year-old male monozygotic twins. Our finding of discordance in these identical twins suggests that a postconceptual mutation, or epigenetic change and/or an environmental factor may be involved in the cause of Sotos syndrome.

This study was undertaken to ascertain the prevalence of the persistent cavum septi pellucidi in children and adults by magnetic resonance imaging (MRI) and to compare the clinical indications for neuroimaging in the two age groups as a measure of group selection bias. All scans performed at West Virginia University during 1997 were reviewed for the presence of a persistent cavum septi pellucidi. The clinical indications for the MRI study were determined in 100 consecutive adult (17 years of age or older) and 100 consecutive pediatric (younger than 17 years of age) scans. In the 203 pediatric patients the prevalence of a persistent cavum septi pellucidi was 6.9%, and in the 814 adults the prevalence was 2.1%. Mental retardation/developmental delay was the clinical indication for at least 26% of the pediatric patients but was not an indication for neuroimaging in the adult study group. The known association of persistent cavum septi pellucidi with mental retardation and in several groups of patients with conditions clinically characterized by mental dysfunction suggests that the higher prevalence in the pediatric study group may primarily be the result of the patient selection bias operating through the different clinical indications for neuroimaging in the two populations.