TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

Fetal alcohol spectrum disorders: current state of diagnosis and treatment.

PURPOSE OF REVIEW: The purpose of this review is to describe recent findings on the clinical presentation, pathogenesis, and management of fetal alcohol spectrum disorders (FASDs). Alcohol causes a range of physical, developmental, and cognitive impairments on the developing fetus. Individuals exposed to alcohol prenatally have a wide variability in dysmorphic and neurologic features. Hence, a greater understanding of the mechanisms through which alcohol induces defects in the developing fetus is imperative in developing therapies that prevent alcohol-induced effects. RECENT FINDINGS: Current research has focused on leveraging technology to developing tools that can aid in the diagnostic process, defining patterns of neurocognition and neuroimaging specific to FASD, developing neurobehavioral and pharmacologic interventions, and expanding access to care. SUMMARY: FASDs are a common cause of neurodevelopmental impairment in school-age children, and their recognition is essential to provide early interventions in order to optimize the outcome for these individuals when they reach adulthood. Although previously thought to be the result of irreversible neurologic injury from prenatal alcohol exposure, recent evidence points to the benefits of applying principles regarding neuroplasticity in improving the lives for patients and their families.

Differentiating molecular etiologies of Angelman syndrome through facial phenotyping using deep learning.

Angelman syndrome (AS) is caused by several genetic mechanisms that impair the expression of maternally-inherited UBE3A through deletions, paternal uniparental disomy (UPD), UBE3A pathogenic variants, or imprinting defects. Current methods of differentiating the etiology require molecular testing, which is sometimes difficult to obtain. Recently, computer-based facial analysis systems have been used to assist in identifying genetic conditions based on facial phenotypes. We sought to understand if the facial-recognition system DeepGestalt could find differences in phenotype between molecular subtypes of AS. Images and molecular data on 261 individuals with AS ranging from 10 months through 32 years were analyzed by DeepGestalt in a cross-validation model with receiver operating characteristic (ROC) curves generated. The area under the curve (AUC) of the ROC for each molecular subtype was compared and ranked from least to greatest differentiable phenotype. We determined that DeepGestalt demonstrated a high degree of discrimination between the deletion subtype and UPD or imprinting defects, and a lower degree of discrimination with the UBE3A pathogenic variants subtype. Our findings suggest that DeepGestalt can recognize subclinical differences in phenotype based on etiology and may provide decision support for testing.

Ocular measurements in fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) describe a range of physical, behavioral, and neurologic deficits in individuals exposed to alcohol prenatally. Reduced palpebral fissure length is one of the cardinal facial features of FASD. However, other ocular measurements have not been studied extensively in FASD. Using the Fetal Alcohol Syndrome Epidemiologic Research (FASER) database, we investigated how inner canthal distance (ICD), interpupillary distance (IPD), and outer canthal distance (OCD) centiles differed between FASD and non-FASD individuals. We compared ocular measurement centiles in children with FASD to non-FASD individuals and observed reductions in all three centiles for ICD, IPD, and OCD. However, when our non-FASD children who had various forms of growth deficiency (microcephaly, short-stature, or underweight) were compared to controls, we did not observe a similar reduction in ocular measurements. This suggests that reductions in ocular measurements are a direct effect of alcohol on ocular development independent of its effect on growth parameters, which is consistent with animal models showing a negative effect of alcohol on developing neural crest cells. Interpupillary distance centile appeared to be the most significantly reduced ocular measure we evaluated, suggesting it may be a useful measure to be considered in the diagnosis of FASD.

Rubinstein-Taybi syndrome in diverse populations.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.

Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization.

The presynaptic, high-affinity choline transporter is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction. Here we describe an autosomal recessive presynaptic congenital myasthenic syndrome presenting with a broad clinical phenotype due to homozygous choline transporter missense mutations. The clinical phenotype ranges from the classical presentation of a congenital myasthenic syndrome in one patient (p.Pro210Leu), to severe neurodevelopmental delay with brain atrophy (p.Ser94Arg) and extend the clinical outcomes to a more severe spectrum with infantile lethality (p.Val112Glu). Cells transfected with mutant transporter construct revealed a virtually complete loss of transport activity that was paralleled by a reduction in transporter cell surface expression. Consistent with these findings, studies to determine the impact of gene mutations on the trafficking of the Caenorhabditis elegans choline transporter orthologue revealed deficits in transporter export to axons and nerve terminals. These findings contrast with our previous findings in autosomal dominant distal hereditary motor neuropathy of a dominant-negative frameshift mutation at the C-terminus of choline transporter that was associated with significantly reduced, but not completely abrogated choline transporter function. Together our findings define divergent neuropathological outcomes arising from different classes of choline transporter mutation with distinct disease processes and modes of inheritance. These findings underscore the essential role played by the choline transporter in sustaining acetylcholine neurotransmission at both central and neuromuscular synapses, with important implications for treatment and drug selection.

Noonan syndrome in diverse populations.

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely spaced eyes and low-set ears in 80% or greater of participants, short stature in more than 70%, and pulmonary stenosis in roughly half of study individuals. Using facial analysis technology, we compared 161 Caucasian, African, Asian, and Latin American individuals with NS with 161 gender and age matched controls and found that sensitivity was equal to or greater than 94% for all groups, and specificity was equal to or greater than 90%. In summary, we present consistent clinical findings from global populations with NS and additionally demonstrate how facial analysis technology can support clinicians in making accurate NS diagnoses. This work will assist in earlier detection and in increasing recognition of NS throughout the world.

Down syndrome in diverse populations.

Down syndrome is the most common cause of cognitive impairment and presents clinically with universally recognizable signs and symptoms. In this study, we focus on exam findings and digital facial analysis technology in individuals with Down syndrome in diverse populations. Photos and clinical information were collected on 65 individuals from 13 countries, 56.9% were male and the average age was 6.6 years (range 1 month to 26 years; SD = 6.6 years). Subjective findings showed that clinical features were different across ethnicities (Africans, Asians, and Latin Americans), including brachycephaly, ear anomalies, clinodactyly, sandal gap, and abundant neck skin, which were all significantly less frequent in Africans (P < 0.001, P < 0.001, P < 0.001, P < 0.05, and P < 0.05, respectively). Evaluation using a digital facial analysis technology of a larger diverse cohort of newborns to adults (n = 129 cases; n = 132 controls) was able to diagnose Down syndrome with a sensitivity of 0.961, specificity of 0.924, and accuracy of 0.943. Only the angles at medial canthus and ala of the nose were common significant findings amongst different ethnicities (Caucasians, Africans, and Asians) when compared to ethnically matched controls. The Asian group had the least number of significant digital facial biometrics at 4, compared to Caucasians at 8 and Africans at 7. In conclusion, this study displays the wide variety of findings across different geographic populations in Down syndrome and demonstrates the accuracy and promise of digital facial analysis technology in the diagnosis of Down syndrome internationally. © 2016 Wiley Periodicals, Inc.

22q11.2 deletion syndrome in diverse populations.

22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P < 0.05). However, when Africans were removed from analysis, six additional clinical features were found to be independent of ethnicity (P ≥ 0.05). Using facial analysis technology, we compared 156 Caucasians, Africans, Asians, and Latin American individuals with 22q11.2 DS with 156 age and gender matched controls and found that sensitivity and specificity were greater than 96% for all populations. In summary, we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world.

Congenital Amegakaryocytic Thrombocytopenia: A Case Series Indicating 2 Founder Variants in the Mississippi Band of Choctaw Indians.

Congenital amegakaryocytic thrombocytopenia is a rare disorder causing thrombocytopenia that progresses to pancytopenia and bone marrow failure if untreated. It is caused by variants in the MPL gene which encodes the thrombopoeitin receptor. In this report, we review 5 cases of congenital amegakaryocytic thrombocytopenia, all of whom belong to the Mississippi Band of Choctaw Indians. There are 2 common variants in these cases: R90X and R537W. One variant was previously reported only once and had unclear significance at that time. With these variants identified, we hope to improve screening that results in earlier diagnosis in the Choctaw population in the future.

Success rates for consent and collection of prenatal biological specimens in an epidemiologic survey of child health.

BACKGROUND: The National Children's Study (NCS) Vanguard Study began enrollment in January 2009 as an initial pilot study for a planned large-scale, longitudinal U.S. cohort study of the effect of environmental influences on child health and development, with biological and environmental sample collection conducted in seven locations from April 2009 to October 2010. We sought to determine rates of consent for, and success of collection of, maternal and paternal biospecimens before and during pregnancy in the NCS Vanguard Study. METHODS: Samples of blood, saliva, vaginal swabs, urine, hair, and nails were collected before and during pregnancy. All specimens were sent to a central repository for processing, storage, and quality assessment. RESULTS: Of 780 pregnant women asked to consent to sample collection, 773 (>99%) agreed, and of 295 nonpregnant women, 292 (99%) agreed. Of 440 fathers asked to consent to sample collection, 435 (99%) agreed. Frequency of successful collection of biospecimens varied depending on sample and visit type. In descending order, the ranges over all visit types of the proportion of expected samples successfully collected from women were: urine, 92.5 to 95.7%; hair, 89.6 to 92.5%; vaginal swab, 84.2 to 88.5%; blood, 74.9 to 78.5%; 2-day saliva, 65.8 to 81.6%; and nails, 76.4 to 76.7%. For fathers, rates were highest for urine (94.9%) and lowest for hair (63.0%). CONCLUSION: High rates of consent for and collection of a wide variety of biospecimens can be achieved in prospective epidemiologic cohort studies of pregnant women. Ease of sample collection may be a primary factor influencing successful biospecimen collection.

Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome.

Genitopatellar syndrome (GPS) is a skeletal dysplasia with cerebral and genital anomalies for which the molecular basis has not yet been determined. By exome sequencing, we found de novo heterozygous truncating mutations in KAT6B (lysine acetyltransferase 6B, formerly known as MYST4 and MORF) in three subjects; then by Sanger sequencing of KAT6B, we found similar mutations in three additional subjects. The mutant transcripts do not undergo nonsense-mediated decay in cells from subjects with GPS. In addition, human pathological analyses and mouse expression studies point to systemic roles of KAT6B in controlling organismal growth and development. Myst4 (the mouse orthologous gene) is expressed in mouse tissues corresponding to those affected by GPS. Phenotypic differences and similarities between GPS, the Say-Barber-Biesecker variant of Ohdo syndrome (caused by different mutations of KAT6B), and Rubinstein-Taybi syndrome (caused by mutations in other histone acetyltransferases) are discussed. Together, the data support an epigenetic dysregulation of the limb, brain, and genital developmental programs.

Assessment of congenital anomalies in infants born to pregnant women enrolled in clinical trials.

In 2011 and 2012, the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, held a series of meetings to provide guidance to investigators regarding study design of clinical trials of vaccines and antimicrobial medications that enroll pregnant women. Assessment of congenital anomalies among infants born to women enrolled in these trials was recognized as a challenging issue, and a workgroup with expertise in epidemiology, pediatrics, genetics, dysmorphology, clinical trials, and infectious diseases was formed to address this issue. The workgroup considered 3 approaches for congenital anomalies assessment that have been developed for use in other studies: (1) maternal report combined with medical records review, (2) standardized photographic assessment and physical examination by a health professional who has received specific training in congenital anomalies, and (3) standardized physical examination by a trained dysmorphologist (combined with maternal interview and medical records review). The strengths and limitations of these approaches were discussed with regard to their use in clinical trials. None of the approaches was deemed appropriate for use in all clinical trials. Instead, the workgroup acknowledged that decisions regarding the optimal method of assessment of congenital anomalies will likely vary depending on the clinical trial, its setting, and the agent under study; in some cases, a combination of approaches may be appropriate. The workgroup recognized the need for more research on approaches to the assessment of congenital anomalies to better guide investigators in optimal design of clinical trials that enroll pregnant women.

Neuromotor synapses in Escobar syndrome.

The Escobar variant of multiple pterygium syndrome (OMIM #265000) is a rare, autosomal recessive disorder associated with mutations in the γ-subunit of the nicotinic acetylcholine receptor (CHRNG). CHRNG is expressed in fetal muscle during motor development and contributes to the formation of neuromuscular junctions (NMJs). Anomalies in NMJ structure and function have not been investigated in patients with Escobar syndrome. We report five patients identified as having Escobar syndrome, from four families. In three families, the same mutation (c.459dupA) was identified in CHRNG. A biopsy from brachioradialis muscle was collected from a patient from one of these families and analyzed for NMJ organization using fluorescence microscopy. Compared to spinalis muscle from control patients with idiopathic scoliosis or cerebral palsy (CP), the patient with Escobar syndrome had a significantly higher degree of acetylcholine receptor present outside acetylcholinesterase and significantly less acetylcholinesterase outside acetylcholine receptors. Given the role of the acetylcholine receptor γ-subunit in fetal neuromuscular signal transduction and in establishing the primary encounter of muscle and motor nerve terminal, the CHRNG mutations described in Escobar syndrome may cause a broader disruption of postsynaptic proteins and result in aberrant development of the NMJ due to impaired prenatal neuromuscular transmission and/or abnormal neuromuscular synaptogenesis.

FOXP1 mutations cause intellectual disability and a recognizable phenotype.

Mutations in FOXP1, located at 3p13, have been reported in patients with global developmental delay (GDD), intellectual disability (ID), and speech defects. Mutations in FOXP2, located at 7q31, are well known to cause developmental speech and language disorders, particularly developmental verbal dyspraxia (DVD). FOXP2 has been shown to work co-operatively with FOXP1 in mouse development. An overlap in FOXP1 and FOXP2 expression, both in the songbird and human fetal brain, has suggested that FOXP1 may also have a role in speech and language disorders. We report on a male child with a 0.19 MB intragenic deletion that is predicted to result in haploinsufficiency of FOXP1. Review of our patient and others reported in the literature reveals an emerging phenotype of GDD/ID with moderate to severe speech delay where expressive speech is most severely affected. DVD appears not to be a distinct feature in this group. Facial features include a broad forehead, downslanting palpebral fissures, a short nose with broad tip, relative or true macrocephaly, a frontal hair upsweep and prominent digit pads. Autistic traits and other behavioral problems are likely to be associated with haploinsufficiency of FOXP1. Congenital malformations may be associated.

Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks.

Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high-resolution arrays in patients who carry a loss (n = 18) or a gain (n = 1) of sub-band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein-protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5-12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks.

Large contiguous gene deletions in Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.

5q14.3 neurocutaneous syndrome: a novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C.

Haploinsufficiency of RASA1, located on chromosome 5q14.3, has been identified as the etiology underlying the disorder capillary malformation-arteriovenous malformation (CM-AVM). Recently, haploinsufficiency of MEF2C, located 1.33 Mb distal to RASA1 on chromosome 5q14.3, has been implicated as the genetic etiology underlying a complex array of deficits including mental retardation, hypotonia, absent speech, seizures, and brain anomalies. Here we report a patient who is haploinsufficient in both RASA1 and MEF2C who presents with dermatologic and neurologic abnormalities that constitute a 5q14.3 neurocutaneous syndrome. This finding highlights the need to assess for CM-AVM in patients with neurologic features consistent with MEF2C haploinsufficiency, and vice versa.

Chromosome 22q11.2 deletion syndrome in African-American patients: a diagnostic challenge.

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under-diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African-American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About 3/4 of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African-American individuals with this syndrome, due to both altered frequencies of major anomalies and a non-classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African-American individuals.

Nicolaides-Baraitser syndrome: Delineation of the phenotype.

Nicolaides-Baraitser syndrome (NBS) is an infrequently described condition, thus far reported in five cases. In order to delineate the phenotype and its natural history in more detail, we gathered data on 18 hitherto unreported patients through a multi-center collaborative study, and follow-up data of the earlier reported patients. A detailed comparison of the 23 patients is provided. NBS is a distinct and recognizable entity, and probably has been underdiagnosed until now. Main clinical features are severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some of the features are progressive with time. The main differential diagnosis is Coffin-Siris syndrome. There is no important gender difference in occurrence and frequency of the syndrome, and all cases have been sporadic thus far. Microarray analysis performed in 14 of the patients gave normal results. Except for the progressive nature there are no clues to the cause.