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Neurofibromatosis type 1 is an autosomal dominant multisystemic disease caused by mutation of the neurofibromin (NF1) gene located on chromosome 17q11. We report a case of Neurofibromatosis 1 with ambiguous genitalia, giant congenital melanocytic nevus, and associated subpulmonic outlet ventricular septal defect, hitherto unreported in sub‐Saharan Africa. In addition, a literature review of congenital heart diseases associated with Neurofibromatosis 1 is presented. [ABSTRACT FROM AUTHOR]

Hajdu‐Cheney syndrome is an ultra‐rare autosomal dominant disorder caused by a heterozygous variant in NOTCH2 gene. Characteristic features include osteolysis, distinct facial appearance, skull deformity, joint laxity, osteoporosis, and short stature. Associated abnormalities are congenital heart disease, congenital defects of the kidney, and neurological problems. Here, we present the first reported case of an African child with a variant in NOTCH2 gene and features of Hajdu‐Cheney syndrome in whom we detected a congenital heart defect that has not been previously reported in association with the syndrome. To appropriately characterize this disease and document correct proportion of cardiovascular malformation associations, echocardiography is recommended for all cases of Hajdu Cheney syndrome. [ABSTRACT FROM AUTHOR]

POLE is a pleiotropic gene with phenotypic expression of pathogenic variants depending on the type of variant, impact on the protein, and mode of inheritance. Heterozygous missense variants located within the exonuclease domain have been shown to result in polymerase proofreading‐associated polyposis (PPAP) which is characterized by an increased risk for colon polyps and colorectal cancer. Biallelic variants resulting in markedly reduced amounts of normal protein have been reported in two separate recessive pediatric syndromes: facial dysmorphism, immunodeficiency, livedo, and short stature as well as intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genital anomalies. Here we report two siblings identified to have POLE c.1686 + 32C > G in trans with POLE p.(Glu709*) via exome sequencing. A detailed review of the reported phenotypes in these two siblings and from available literature revealed that individuals with biallelic POLE pathogenic variants resulting in partial loss‐of‐function present with a similar phenotype: short stature and facial dysmorphism with or without immunodeficiency. These data suggest a phenotypic continuum between the previously reported POLE‐related recessive disorders. [ABSTRACT FROM AUTHOR]

Objective: Report a single‐center 12‐year experience in the fetal diagnosis of diencephalic‐mesencephalic junction dysplasia (DMJD) to expand the phenotype with Magnetic resonance imaging (MRI)‐based classification, evaluate genetic etiologies, and ascertain outcomes. Methods: Retrospective medical record and imaging review of all fetal MRI exams with DMJD were performed at our institution. Results: Thirty‐three pregnancies with fetal MRI findings of DMJD at 24 (18–37) weeks gestational age were studied; 70% were referred for fetal hydrocephalus. Three fetal MRI patterns were recognized. Type A (butterfly/hypothalamus‐midbrain union) was seen in two cases (6%), Type B (partial thalamus‐midbrain union) in 22 fetuses (70%), and Type C (complete/near complete midbrain‐thalamic continuity) in nine fetuses (24%). L1CAM mutations were identified in four cases, and biallelic VRK1 variants in another. Among 14 live‐born cases, 11 survived infancy, and 10 underwent postnatal brain MRI which confirmed the fetal MRI diagnosis in all but one case. Development was delayed in all surviving infants, most with additional neurological sequelae. Conclusions: DMJD may be identified by prenatal MRI as early as 18 weeks gestation. We propose three distinct phenotypic forms of DMJD, Types A–C. Next‐generation sequencing provides an underlying molecular diagnosis in some patients, but further studies on associated genetic diagnoses and clinical outcomes are indicated. Key Points: What's already known about this topic? Diencephalic‐mesencephalic junction dysplasia Types A and B had been previously reported in small case series. Pathogenic variants in PCDH12 and L1CAM have been implicated in the development of diencephalic‐mesencephalic junction dysplasia. What does this study add? Newly identified features on prenatal MRI support the definition of an additional subtype, diencephalic‐mesencephalic junction dysplasia Type C. Pregnancy and postnatal outcomes and genetic causes of diencephalic‐mesencephalic junction dysplasia are described. [ABSTRACT FROM AUTHOR]

Objective: Report a single-center 12-year experience in the fetal diagnosis of diencephalic-mesencephalic junction dysplasia (DMJD) to expand the phenotype with Magnetic resonance imaging (MRI)-based classification, evaluate genetic etiologies, and ascertain outcomes.Methods: Retrospective medical record and imaging review of all fetal MRI exams with DMJD were performed at our institution.Results: Thirty-three pregnancies with fetal MRI findings of DMJD at 24 (18-37) weeks gestational age were studied; 70% were referred for fetal hydrocephalus. Three fetal MRI patterns were recognized. Type A (butterfly/hypothalamus-midbrain union) was seen in two cases (6%), Type B (partial thalamus-midbrain union) in 22 fetuses (70%), and Type C (complete/near complete midbrain-thalamic continuity) in nine fetuses (24%). L1CAM mutations were identified in four cases, and biallelic VRK1 variants in another. Among 14 live-born cases, 11 survived infancy, and 10 underwent postnatal brain MRI which confirmed the fetal MRI diagnosis in all but one case. Development was delayed in all surviving infants, most with additional neurological sequelae.Conclusions: DMJD may be identified by prenatal MRI as early as 18 weeks gestation. We propose three distinct phenotypic forms of DMJD, Types A-C. Next-generation sequencing provides an underlying molecular diagnosis in some patients, but further studies on associated genetic diagnoses and clinical outcomes are indicated. [ABSTRACT FROM AUTHOR]

Background: Holoprosencephaly is the most common malformation of the forebrain (1 in 250 embryos) with severe consequences for fetal and child development. This study evaluates nongenetic factors associated with holoprosencephaly risk, severity, and gene–environment interactions. Methods: For this retrospective case control study, we developed an online questionnaire focusing on exposures to common and rare toxins/toxicants before and during pregnancy, nutritional factors, maternal health history, and demographic factors. Patients with holoprosencephaly were primarily ascertained from our ongoing genetic and clinical studies of holoprosencephaly. Controls included children with Williams‐Beuren syndrome (WBS) ascertained through online advertisements in a WBD support group and fliers. Results: Difference in odds of exposures between cases and controls as well as within cases with varying holoprosencephaly severity were studied. Cases included children born with holoprosencephaly (n = 92) and the control group consisted of children with WBS (n = 56). Pregnancy associated risk associated with holoprosencephaly included maternal pregestational diabetes (9.2% of cases and 0 controls, p =.02), higher alcohol consumption (adjusted odds ratio [aOR], 1.73; 95% CI, 0.88–15.71), and exposure to consumer products such as aerosols or sprays including hair sprays (aOR, 2.46; 95% CI, 0.89–7.19). Significant gene–environment interactions were identified including for consumption of cheese (p <.05) and espresso drinks (p =.03). Conclusion: The study identifies modifiable risk factors and gene–environment interactions that should be considered in future prevention of holoprosencephaly. Studies with larger HPE cohorts will be needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Pesticide exposure during susceptible windows and at certain doses are linked to numerous birth defects. Early experimental evidence suggests an association between active ingredients in pesticides and holoprosencephaly (HPE), the most common malformation of the forebrain in humans (1 in 250 embryos). No human studies to date have examined the association. This study investigated pesticides during multiple windows of exposure and fetal risk for HPE. It is hypothesized that pre-conception and early pregnancy, the time of brain development in utero, are the most critical windows of exposure.Methods: A questionnaire was developed for this retrospective case-control study to estimate household, occupational, and environmental pesticide exposures. Four windows of exposure were considered: preconception, early, mid and late pregnancy. Cases were identified through the National Human Genome Research Institute's ongoing clinical studies of HPE. Similarly, controls were identified as children with Williams-Beuren syndrome, a genetic syndrome also characterized by congenital malformations, but etiologically unrelated to HPE. We assessed for differences in odds of exposures to pesticides between cases and controls.Results: Findings from 91 cases and 56 controls showed an increased risk for HPE with reports of maternal exposure during pregnancy to select pesticides including personal insect repellants (adjusted odds ratio (aOR) 2.89, confidence interval (CI): 0.96-9.50) and insecticides and acaricides for pets (aOR 3.84, CI:1.04-16.32). Exposure to household pest control products during the preconception period or during pregnancy was associated with increased risk for HPE (aOR 2.60, OR: 0.84-8.68). No associations were found for occupational exposures to pesticides during pregnancy (aOR: 1.15, CI: 0.11-11.42), although exposure rates were low. Higher likelihood for HPE was also observed with residency next to an agricultural field (aOR 3.24, CI: 0.94-12.31).Conclusions: Observational findings are consistent with experimental evidence and suggest that exposure to personal, household, and agricultural pesticides during pregnancy may increase risk for HPE. Further investigations of gene by environment interactions are warranted. [ABSTRACT FROM AUTHOR]

Background: Noonan syndrome is a common genetic syndrome caused by pathogenic variants in genes in the Ras/MAPK signaling pathway. The medical literature has an abundance of studies on Noonan syndrome, but few are from the African continent. Methods: The medical literature was searched for studies on Noonan syndrome from the African continent and these reports were added to our experience in Africa. Facial analysis was reviewed from two previous reports from our group using a support vector machine (SVM) algorithm and an analysis using the Face2Gene convolutional neural network technology. Results: Individuals with Noonan syndrome from reports in African populations have the classic phenotype characteristics including typical minor facial anomalies such as widely spaced eyes (31–100%), short stature (71–100%), and congenital heart disease with pulmonary stenosis found in 24–100% of patients. Similarly, the genotypes are similar with the majority of variants occurring in the gene PTPN11 (72%) and 36% of these variants occurred in the amino acid residue Asn308, which is most commonly found in other populations. The two separate facial analysis algorithms successfully discriminated Africans with NS from unaffected matched individuals with area under the curve (AUC) of the receiver operator characteristic of 0.94 (SVM) and 0.979 for the Face2Gene research methodology. Conclusion: Few studies characterizing Noonan syndrome in Africans have been conducted, highlighting the need for more genetic and genomic research in African populations. Available clinical data, genotypes, and facial analysis technology data show that individuals of African descent with NS can be efficiently diagnosed using available standards. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p <.001) was found for TS versus general population controls and 0.925 (p <.001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome. [ABSTRACT FROM AUTHOR]

Purpose: Turner syndrome (TS) is the most common sex chromosome disorder in women and is associated with a higher than expected death rate secondary to cerebrovascular disease, including stroke. This study evaluates the cerebral vascular anatomy of individuals with TS. Methods: Twenty‐one women with TS had brain magnetic resonance angiography (MRA). These MRAs were evaluated in a blinded manner with a control group of 25 men and 25 women who had MRA imaging for multiple indications including migraine headaches, psychiatric disorders, and seizures. Results: Twenty‐nine percent of women with TS were missing an A1 segment of the anterior cerebral artery (ACA) compared to 0% in the control group (p < .001). There were no other significant differences in the circle of Willis (COW) in women with TS compared with the control group. A complete COW was found in 3 of 21 (14%) of women with TS and 12 of 47 (26%) controls (p = .36). Conclusion: Women with TS have a significantly different intracranial vascular anatomy, specifically the absence of the A1 segment of the ACA when compared to male and female controls. More research in brain imaging in women with TS and stroke and other cerebrovascular diseases is needed to determine the clinical significance of this anomaly. [ABSTRACT FROM AUTHOR]

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features. [ABSTRACT FROM AUTHOR]

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly. [ABSTRACT FROM AUTHOR]

Lysine methyltransferase 2D (KMT2D; OMIM 602113) encodes a histone methyltransferase involved in transcriptional regulation of the beta‐globin and estrogen receptor as part of a large protein complex known as activating signal cointegrator‐2‐containing complex (ASCOM). Heterozygous germline mutations in the KMT2D gene are known to cause Kabuki syndrome (OMIM 147920), a developmental multisystem disorder. Neither holoprosencephaly nor other defects in human forebrain development have been previously associated with Kabuki syndrome. Here we report two patients diagnosed with alobar holoprosencephaly in their antenatal period with de novo monoallelic KMT2D variants identified by trio‐based exome sequencing. The first patient was found to have a stop‐gain variant c.12565G>T (p.Gly4189*), while the second patient had a missense variant c.5A>G (p.Asp2Gly). Phenotyping of each patient did not reveal any age‐related feature of Kabuki syndrome. These two cases represent the first report on association between KMT2D and holoprosencephaly. [ABSTRACT FROM AUTHOR]

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Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes—NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide. [ABSTRACT FROM AUTHOR]

Inborn errors of metabolism (IEM), although individually rare, occur in 1 out of every 1,500 births. The first opportunity to detect IEM occurs during preconception counseling, when pregnant women and couples considering future pregnancies can undergo carrier screening. For individuals of all ethnic backgrounds, the screening includes testing for a variety of IEM and non-IEM. For individuals of Ashkenazi Jewish descent, carrier screening, per the American College of Medical Genetics and Genomics, also includes testing for Tay-Sachs disease and four other IEM. Inborn errors of metabolism can present in utero; in newborns; or in children, adolescents, and adults. Some IEM can be detected in utero with the use of ultrasonography. Most commonly, IEM are detected at newborn screening. Expanded newborn screening, which now includes 34 core conditions, allows for diagnosis in the newborn period and provides the opportunity for early institution of available treatments. However, some newborns present with symptoms consistent with an IEM before the availability of pending newborn screening results or present with symptoms attributable to an IEM not detectable with screening. Such situations are medical emergencies requiring immediate consultation with a metabolic specialist. If a delay occurs in obtaining consultation, initial treatment involves discontinuing feeding and providing high-rate glucose infusions. Some IEM present later in life. Children may develop and present with dysmorphic facial features. In some cases, symptoms may not appear until adolescence or adulthood when patients have residual enzyme activity that allows for slow accumulation of toxic molecules over time. Long-term treatments are effective for some IEM. Treatments include dietary restrictions and enzyme-replacement therapies. [ABSTRACT FROM AUTHOR]

Background: Congenital heart diseases (CHDs) affect ~1% of newborns and are a significant cause of morbidity and mortality in children. We present the clinical epidemiology of CHD as seen in a large university medical center in Nigeria. Methods: Participants were 767 children with echocardiographically confirmed CHD seen over a 5‐year period at the Lagos University Teaching Hospital, Nigeria. Results: Clinical presentation was often late with just over half (58.1%) presenting in infancy. The male:female distribution was 1:1. The predominant types of cardiac lesion seen were septal defects (43%), conotruncal defects (23.7%), atrioventricular septal defects (9.8%), and right ventricular outflow tract obstruction (7.3%). Cyanotic CHD was seen in 28.4% of cases and the single most common cyanotic CHD was Tetralogy of Fallot (13.4%). Children with cyanotic CHD were older (p = .002), had more severe lesions (p < .0001) and were more likely to have cardiac intervention (p < .0001). Extracardiac malformations were present in nearly one‐third of the children. Syndromes associated with CHD were identified in 15.5% of the children and included Down syndrome (11.9%), congenital rubella syndrome (1.0%), and Marfan syndrome (0.7%). Conclusions: This study is a large case series of CHD from a single site in sub‐Saharan Africa utilizing clinical, epidemiological, and developmental considerations. It provides a rich and up‐to‐date description of the clinical epidemiology of CHD in Nigerian children while yielding data that could be useful for designing genetic, molecular, and biomarker studies. [ABSTRACT FROM AUTHOR]

Abstract: Here, we applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 333 probands to rank their relative significance as causes for holoprosencephaly (HPE). We now show that comparisons of variant transmission versus nontransmission among 136 HPE Trios indicates some reported genes now lack confirmation, while novel genes are implicated. Furthermore, we demonstrate that variation of modest intrinsic effect can synergize with these driver mutations as gene modifiers. [ABSTRACT FROM AUTHOR]

Williams–Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P‐value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses. [ABSTRACT FROM AUTHOR]

Holoprosencephaly (HPE) is failure of the forebrain to divide completely during embryogenesis. Incomplete penetrance has not been reported previously in SIX3 whole gene deletions, which are known to cause HPE. Both chromosomal microarray and whole exome sequencing (WES) were used to evaluate families with inherited HPE. Two families showed inherited deletions that contain SIX3 and were incompletely penetrant for HPE. Using WES, we ruled out parental mosaicism, a SIX3 hypomorph, and clinically significant variants in genes that are known to interact with SIX3 as causes of incomplete penetrance. We demonstrate the importance of molecular cascade testing in families with HPE and we answer important questions about incomplete penetrance. [ABSTRACT FROM AUTHOR]

Background: Congenital heart disease (CHD) is a common birth defect affecting approximately 1% of newborns. Great progress has been made in elucidating the genetic aetiology of CHD with advances in genomic technology, which we leveraged in recovering a new pathway affecting heart development in humans previously known to affect heart development in an animal model. Methods: Four hundred and sixteen individuals from Thailand and the USA diagnosed with CHD and/or congenital diaphragmatic hernia were evaluated with chromosomal microarray and whole exome sequencing. The DECIPHER Consortium and medical literature were searched for additional patients. Murine hearts from ENU-induced mouse mutants and transgenic mice were evaluated using both episcopic confocal histopathology and troponin I stained sections. Results: Loss of function ROBO1 variants were identified in three families; each proband had a ventricular septal defect, and one proband had tetralogy of Fallot. Additionally, a microdeletion in an individual with CHD was found in the medical literature. Mouse models showed perturbation of the Slit-Robo signalling pathway, causing septation and outflow tract defects and craniofacial anomalies. Two probands had variable facial features consistent with the mouse model. Conclusion: Our findings identify Slit-Robo as a significant pathway in human heart development and CHD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome characterized by mostly benign tumors of the brain, skin, heart, kidney, and eye. Aberrations in the genes TSC1 and TSC2 which encode hamartin and tuberin, respectively, cause TSC. Because disease manifestations develop over time, early diagnosis and intervention are imperative for patients. TSC is not well described in patients from sub‐Saharan Africa or of black African ancestry. Here, we report on a 4‐year‐old Nigerian boy with skin lesions and cardiac anomalies associated with TSC. Furthermore, we note that in areas with limited resources for genetic diagnoses, the common skin manifestations found in TSC may be especially useful clinical markers. [ABSTRACT FROM AUTHOR]

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty-five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% ( P = 0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x-rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month-old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS-MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Limb body wall complex ( LBWC) and amniotic band sequence ( ABS) are multiple congenital anomaly conditions with craniofacial, limb, and ventral wall defects. LBWC and ABS are considered separate entities by some, and a continuum of severity of the same condition by others. The etiology of LBWC/ ABS remains unknown and multiple hypotheses have been proposed. One individual with features of LBWC and his unaffected parents were whole exome sequenced and Sanger sequenced as confirmation of the mutation. Functional studies were conducted using morpholino knockdown studies followed by human mRNA rescue experiments. Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC. Morpholino knockdown of iqck mRNA in the zebrafish showed ventral defects including failure of ventral fin to develop and cardiac edema. Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish. This study supports a genetic etiology for LBWC/ ABS, or potentially a new syndrome. [ABSTRACT FROM AUTHOR]

Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural 'Turner Resource Network (TRN) Symposium' brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome;, investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]