Publications by authors named "Melanie A Manning"

45 Publications

Increased Autoimmunity in Individuals With Down Syndrome and Moyamoya Disease.

Front Neurol 2021 8;12:724969. Epub 2021 Sep 8.

Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, United States.

To determine if elevated rates of autoimmune disease are present in children with both Down syndrome and moyamoya disease given the high rates of autoimmune disease reported in both conditions and unknown etiology of angiopathy in this population. A multi-center retrospective case-control study of children with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome without cerebrovascular disease was performed. Outcome measures included presence of autoimmune disease, presence of autoantibodies and angiopathy severity data. Comparisons across groups was performed using the Kruskal-Wallis, χ2 and multivariate Poisson regression. The prevalence of autoimmune disease were 57.7, 20.3, and 35.3% in persons with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome only groups, respectively ( < 0.001). The prevalence of autoimmune disease among children with Down syndrome and moyamoya syndrome is 3.2 times ( < 0.001, 95% CI: 1.82-5.58) higher than the idiopathic moyamoya group and 1.5 times ( = 0.002, 95% CI: 1.17-1.99) higher than the Down syndrome only group when adjusting for age and sex. The most common autoimmune diseases were thyroid disorders, type I diabetes and Celiac disease. No individuals with idiopathic moyamoya disease had more than one type of autoimmune disorder while 15.4% of individuals with Down syndrome and moyamoya syndrome and 4.8% of individuals with Down syndrome only had >1 disorder ( = 0.05, 95%CI: 1.08-6.08). This study reports elevated rates of autoimmune disease in persons with Down syndrome and moyamoya syndrome providing a nidus for study of the role of autoimmunity in angiopathy in this population.
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http://dx.doi.org/10.3389/fneur.2021.724969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455812PMC
September 2021

Estimating the community prevalence, child traits, and maternal risk factors of fetal alcohol spectrum disorders (FASD) from a random sample of school children.

Drug Alcohol Depend 2021 10 2;227:108918. Epub 2021 Aug 2.

Department of Pediatrics, University of Arizona College of Medicine, Tucson, AZ, United States; Sanford Children's Genomic Medicine Consortium, Sanford Health, Sioux Falls, SD, United States.

Objective: Utilize a random sample to estimate the prevalence, child traits, and maternal risk for fetal alcohol spectrum disorders (FASD) in a Southeastern United States county.

Methods: From all first-grade students (n = 1073) a simple random sample was drawn, and 32 % (n = 231) were consented. All 231 children were examined for dysmorphology and growth, 84 were tested and rated on neurobehavior, and 72 mothers were interviewed for maternal risk.

Results: Significant differences (α = .05) between the physical traits of children diagnosed with FASD and the entire sample were height, weight, head circumference, body mass index, and total dysmorphology scores, and all three cardinal features of fetal alcohol syndrome: palpebral fissure length, smooth philtrum, and narrow vermilion. Intellectual function and inhibition were not significantly different between FASD and typically-functioning children, but two executive function measures and one visual/spatial measure approached significance (α = .10). Three behavioral measures were significantly worse for the FASD group: parent-rated problems of communication, daily living, and socialization. Significant maternal risk factors reported were postpartum depression, frequency of drinking, and recovery from problem drinking. The prevalence of FASD was 71.4 per 1,000 or 7.1 %. This rate falls clearly within the prevalence range identified in eight larger samples of other communities in the Collaboration on FASD Prevalence (CoFASP) study in four regions of the United States.

Conclusion: Careful and detailed clinical evaluation of children from small random samples can be useful for estimating the prevalence and traits of FASD in a community.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499999PMC
October 2021

Gestational age and birth growth parameters as early predictors of fetal alcohol spectrum disorders.

Alcohol Clin Exp Res 2021 08 2;45(8):1624-1638. Epub 2021 Aug 2.

Gillings School of Global Public Health, Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA.

Objective: To investigate gestational age and growth at birth as predictors of fetal alcohol spectrum disorders (FASD).

Methods: The sample analyzed here comprises 737 randomly selected children who were assessed for growth, dysmorphology, and neurobehavior at 7 years of age. Maternal interviews were conducted to ascertain prenatal alcohol exposure and other maternal risk factors. Birth data originated from clinic records and the data at 7 years of age originated from population-based, in-school studies. Binary linear regression assessed the relationship between preterm birth, small for gestational age (SGA), and their combination on the odds of a specific FASD diagnosis or any FASD.

Results: Among children diagnosed with FASD at 7 years of age (n = 255), a review of birth records indicated that 18.4% were born preterm, 51.4% were SGA, and 5.9% were both preterm and SGA. When compared to non-FASD controls (n = 482), the birth percentages born preterm, SGA, and both preterm and SGA were respectively 12.0%, 27.7%, and 0.5%. Mothers of children with FASD reported more drinking during all trimesters, higher gravidity, lower educational attainment, and older age at pregnancy. After controlling for usual drinks per drinking day in the first trimester, number of trimesters of drinking, maternal education, tobacco use, and maternal age, the odds ratio of an FASD diagnosis by age 7 was significantly associated with SGA (OR = 2.16, 95% CI: 1.35 to 3.45). SGA was also significantly associated with each of the 3 most common specific diagnoses within the FASD continuum: fetal alcohol syndrome (FAS; OR = 3.1), partial FAS (OR = 2.1), and alcohol-related neurodevelopmental disorder (OR = 2.0).

Conclusion: SGA is a robust early indicator for FASD in this random sample of children assessed at 7 years of age.
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http://dx.doi.org/10.1111/acer.14656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429067PMC
August 2021

Immunohistochemical ALK Expression in Granular Cell Atypical Fibroxanthoma: A Diagnostic Pitfall for ALK-Rearranged Non-neural Granular Cell Tumor.

Am J Dermatopathol 2021 Nov;43(11):831-834

Department of Pathology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA.

Abstract: Atypical fibroxanthoma (AFX) is a neoplasm that most commonly occurs on sun-damaged skin of the head and neck in elderly patients and that usually exhibits indolent clinical behavior with complete excision. The granular cell variant of AFX demonstrates overlapping histopathologic features with dermal non-neural granular cell tumor (NNGCT), which typically arises on the extremities of young to middle aged adults with rare reports of regional metastasis. A subset of NNGCT harbors ALK rearrangements and expresses ALK by immunohistochemistry. Here, we present 2 cases of granular cell AFX occurring on the scalp of males aged 73 and 87 with ALK expression by immunohistochemistry and no evidence of an ALK rearrangement on fluorescence in situ hybridization, representing a diagnostic pitfall for NNGCT.
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http://dx.doi.org/10.1097/DAD.0000000000001931DOI Listing
November 2021

The prevalence, child characteristics, and maternal risk factors for the continuum of fetal alcohol spectrum disorders: A sixth population-based study in the same South African community.

Drug Alcohol Depend 2021 01 13;218:108408. Epub 2020 Nov 13.

Sanford Children's Genomic Medicine Consortium, Sanford Health, and the University of South Dakota Sanford School of Medicine, Department of Pediatrics, 1600 W. 22nd St., Sioux Falls, SD, 57117, United States; Department of Pediatrics and the Center for Applied Genetics and Genomic Medicine, The University of Arizona College of Medicine, 1501 N. Campbell Avenue, Tucson, Arizona, 85724, United States.

Background: Prevalence and characteristics of fetal alcohol spectrum disorders (FASD) have been described previously in this community.

Methods: Active case ascertainment methods were employed in a new cross-sectional study with Revised Institute of Medicine criteria among first grade students (n = 735) via dysmorphology examinations and neurobehavioral assessments. Their mothers were interviewed regarding risk factors. Final diagnoses were assigned via structured case conferences.

Results: Children with fetal alcohol syndrome (FAS), partial FAS (PFAS), and alcohol related-neurodevelopmental disorder (ARND) were significantly different from controls on all cardinal variables, multiple dysmorphology traits and neurobehavioral performance. Mothers of children with FASD reported significantly more drinking before and during pregnancy (mothers of children with FAS reported 7.8 (±6.1) drinks per drinking day (DDD) prior to pregnancy and 5.1 (±5.9) after pregnancy recognition). Distal risk variables for a diagnosis on the continuum of FASD were: lower maternal height, weight, and body mass index; higher gravidity; lower education and household income; and later pregnancy recognition. Alcohol and tobacco remain the only commonly used drugs. Women reporting first trimester drinking of two DDD were 13 times more likely (95 % CI:1.3-133.4) to have a child with FASD than non-drinkers; and those who reported drinking throughout pregnancy were 19.4 times more likely (95 % CI:8.2-46.0) to have a child with FASD.

Conclusion: Seventeen years after the first study in this community, FASD prevalence remains high at 16 %-31 %. The FAS rate may have declined somewhat, but rates of PFAS and ARND seemed to plateau, at a high rate.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756187PMC
January 2021

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Nat Commun 2020 10 1;11(1):4932. Epub 2020 Oct 1.

Oasi Research Institute-IRCCS, Troina, Italy.

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
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http://dx.doi.org/10.1038/s41467-020-18723-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530681PMC
October 2020

Ocular measurements in fetal alcohol spectrum disorders.

Am J Med Genet A 2020 10 17;182(10):2243-2252. Epub 2020 Jul 17.

Department of Genetic Medicine, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.

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.
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http://dx.doi.org/10.1002/ajmg.a.61759DOI Listing
October 2020

Fetal Alcohol Spectrum Disorders in a Midwestern City: Child Characteristics, Maternal Risk Traits, and Prevalence.

Alcohol Clin Exp Res 2020 04 15;44(4):919-938. Epub 2020 Apr 15.

Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota.

Objective: To determine the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers in a Midwestern city.

Methods: Case-control samples were drawn from 2 separate first-grade cohorts (combined N = 4,047) in every city school using different methods. In Cohort Sample 1, all consented small children (≤25th centile on height, weight, and/or head circumference) entered the study along with a random sample from all enrolled students. Cohort Sample 2 was drawn totally at random. Child growth, dysmorphology, and neurobehavior were assessed using the Collaboration on FASD Prevalence (CoFASP) criteria, and mothers were interviewed.

Results: For the samples combined, 891 children received dysmorphology examinations, and 692 were case-conferenced for final diagnosis. Forty-four children met criteria for FASD. Total dysmorphology scores differentiated diagnostic groups: fetal alcohol syndrome (FAS), 16.7; partial FAS, 11.8; alcohol-related neurodevelopmental disorder (ARND), 6.1; and typically developing controls, 4.2. Neurobehavioral tests distinguished children with FASD from controls, more for behavioral problems than cognitive delay. Children with ARND demonstrated the poorest neurobehavioral indicators. An adjusted regression model of usual prepregnancy drinking indicated that maternal reports of 3 drinks per drinking day (DDD) were significantly associated with a FASD diagnosis (p = 0.020, OR = 10.1, 95% CI = 1.44 to 70.54), as were 5 or more DDD (p < 0.001, OR = 26.47, 95% CI = 4.65 to 150.62). Other significant maternal risk factors included the following: self-reported drinking in any trimester; smoking and cocaine use during pregnancy; later pregnancy recognition and later and less prenatal care; lower maternal weight, body mass index (BMI), and head circumference; and unmarried status. There was no significant difference in FASD prevalence by race, Hispanic ethnicity, or socioeconomic status at this site, where the prevalence of FASD was 14.4 to 41.2 per 1,000 (1.4 to 4.1%).

Conclusion: This city displayed the lowest prevalence of FASD of the 4 CoFASP sites. Nevertheless, FASD were common, and affected children demonstrated a common, recognizable, and measurable array of traits.
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http://dx.doi.org/10.1111/acer.14314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166178PMC
April 2020

Fetal Alcohol Spectrum Disorders in a Southeastern County of the United States: Child Characteristics and Maternal Risk Traits.

Alcohol Clin Exp Res 2020 04 15;44(4):939-959. Epub 2020 Apr 15.

Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota.

Objective: To detail the characteristic traits of children with fetal alcohol spectrum disorders (FASDs) and maternal risk factors in a southeastern U.S. County.

Methods: Independent samples were drawn from 2 different cohorts of first-grade students. All consented children (49.8%) were measured for height, weight, and head circumference, and those ≤ 25th centile entered the study along with a random sample drawn from all enrolled students. Study children were examined for physical growth, dysmorphology, and neurobehavior, and their mothers were interviewed.

Results: Total dysmorphology scores discriminated well the physical traits of children across the FASD continuum: fetal alcohol syndrome (FAS) = 15.8, partial FAS (PFAS) = 10.8, alcohol-related neurobehavioral disorder (ARND) = 5.2, and typically developing controls = 4.4. Additionally, a neurobehavioral battery distinguished children with each FASD diagnosis from controls. Behavioral problems qualified more children for FASD diagnoses than cognitive traits. Significant proximal maternal risk variables were as follows: reports of prepregnancy drinking, drinking in any trimester, and comorbid use of other drugs in lifetime and during pregnancy, especially alcohol and marijuana (14.9% among mothers of children with FASD vs. 0.4% for controls). Distal maternal risks included reports of other health problems (e.g., depression), living unmarried with a partner during pregnancy, and a lower level of spirituality. Controlling for other drug use during pregnancy, having a child diagnosed with a FASD was 17.5 times greater for women who reported usual consumption of 3 drinks per drinking day prior to pregnancy than for nondrinking mothers (p < 0.001, 95% CI = 5.1 to 59.9). There was no significant difference in the prevalence of FASD by race, Hispanic ethnicity, or socioeconomic status. The prevalence of FASD was not lower than 17.3 per 1,000, and weighted estimated prevalence was 49.0 per 1,000 or 4.9%.

Conclusion: This site had the second lowest rate in the CoFASP study, yet children with FASD are prevalent.
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http://dx.doi.org/10.1111/acer.14313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169982PMC
April 2020

Fetal Alcohol Spectrum Disorders in a Rocky Mountain Region City: Child Characteristics, Maternal Risk Traits, and Prevalence.

Alcohol Clin Exp Res 2020 04 15;44(4):900-918. Epub 2020 Apr 15.

Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota.

Objective: To document prevalence and traits of children with fetal alcohol spectrum disorders (FASD) and maternal risk factors in a Rocky Mountain city.

Methods: Variations on active case ascertainment methods were used in 2 first-grade cohorts in all city schools. The consent rate was 59.2%. Children were assessed for physical growth, dysmorphology, and neurobehavior and their mothers interviewed.

Results: Thirty-eight children were diagnosed with FASD and compared with 278 typically developing controls. Total dysmorphology scores summarized well the key physical indicators of FASD and defined specific diagnostic groups. On average, children with FASD performed significantly poorer than controls on intellectual, adaptive, learning, attention, and behavioral tasks. More mothers of children with FASD reported drinking prior to pregnancy and in the first and second trimesters, and had partners with drinking problems than mothers of controls; however, reports of comorbid alcohol use and 6 other drugs were similar for mothers of children with FASD and mothers of controls. Mothers of children with FASD were significantly younger at pregnancy, had lower average weight before pregnancy and less education, initiated prenatal clinic visits later, and reported more health problems (e.g., stomach ulcers and accidents). Children with FASD had significantly lower birth weight and more problems at birth, and were less likely to be living with biological mother and father. Controlling for other drug and tobacco use, a FASD diagnosis is 6.7 times (OR = 6.720, 95% CI = 1.6 to 28.0) more likely among children of women reporting prepregnancy drinking of 3 drinks per drinking day (DDD) and 7.6 times (OR = 7.590, 95% CI = 2.0 to 31.5) more likely at 5 DDD. Prevalence of FAS was 2.9-5.8 per 1,000 children, and total FASD was 34.9 to 82.5 per 1,000 children or 3.5 to 8.3% at this site.

Conclusion: This site had the second highest prevalence of FASD of the 4 Collaboration on FASD Prevalence sites and clearly identifiable child and maternal risk traits.
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http://dx.doi.org/10.1111/acer.14315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166196PMC
April 2020

Early-Life Predictors of Fetal Alcohol Spectrum Disorders.

Pediatrics 2019 12 19;144(6). Epub 2019 Nov 19.

Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa;

Background And Objectives: Fetal alcohol spectrum disorders (FASD) comprise the continuum of disabilities associated with prenatal alcohol exposure. Although infancy remains the most effective time for initiation of intervention services, current diagnostic schemes demonstrate the greatest confidence, accuracy, and reliability in school-aged children. Our aims for the current study were to identify growth, dysmorphology, and neurodevelopmental features in infants that were most predictive of FASD at age 5, thereby improving the timeliness of diagnoses.

Methods: A cohort of pregnant South African women attending primary health care clinics or giving birth in provincial hospitals was enrolled in the project. Children were followed longitudinally from birth to 60 months to determine their physical and developmental trajectories ( = 155). Standardized protocols were used to assess growth, dysmorphology, and development at 6 weeks and at 9, 18, 42, and 60 months. A structured maternal interview, including estimation of prenatal alcohol intake, was administered at 42 or 60 months.

Results: Growth restriction and total dysmorphology scores differentiated among children with and without FASD as early as 9 months (area under the receiver operating characteristic curve = 0.777; < .001; 95% confidence interval: 0.705-0.849), although children who were severely affected could be identified earlier. Assessment of developmental milestones revealed significant developmental differences emerging among children with and without FASD between 18 and 42 months. Mothers of children with FASD were significantly smaller, with lower BMIs and higher alcohol intake during pregnancy, than mothers of children without FASD.

Conclusions: Assessment of a combination of growth, dysmorphology, and neurobehavioral characteristics allows for accurate identification of most children with FASD as early as 9 to 18 months.
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http://dx.doi.org/10.1542/peds.2018-2141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889972PMC
December 2019

Fetal Alcohol Spectrum Disorders in a Pacific Southwest City: Maternal and Child Characteristics.

Alcohol Clin Exp Res 2019 12 5;43(12):2578-2590. Epub 2019 Nov 5.

Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California.

Background: There are limited data on the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers from the general population in the United States.

Methods: During the 2012 and 2013 academic years, first-grade children in a large urban Pacific Southwest city were invited to participate in a study to estimate the prevalence of FASD. Children who screened positive on weight, height, or head circumference ≤25th centile or on parental report of developmental concerns were selected for evaluation, along with a random sample of those who screened negative. These children were examined for dysmorphology and neurobehavior and their mothers or collateral sources were interviewed. Children were classified as fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), or No FASD.

Results: A total of 854 children were evaluated; 5 FAS, 44 pFAS, 44 ARND, and 761 No FASD. Children with FAS or pFAS were more likely to have dysmorphic features, and 32/49 (65.3%) of those met criteria for neurobehavioral impairment on cognitive measures with or without behavioral deficits. In contrast, 28/44 (63.6%) of children with ARND met criteria on behavioral measures alone. Mothers of FASD children were more likely to recognize pregnancy later, be unmarried, and report other substance use or psychiatric disorders, but did not differ on age, socioeconomic status, education, or parity. Mothers of FASD children reported more drinks/drinking day each trimester. The risk of FASD was elevated with increasing number of drinks/drinking day prior to pregnancy recognition, even at the level of 1 drink per day (adjusted odds ratio 3.802, 95% confidence interval 1.634, 8.374).

Conclusions: Data from this general population sample in a large urban region in the United States demonstrate the variability of expression of FASD and point to risk and protective factors for mothers in this setting.
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http://dx.doi.org/10.1111/acer.14213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904497PMC
December 2019

Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.

Hum Mutat 2020 01 14;41(1):150-168. Epub 2019 Nov 14.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.
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http://dx.doi.org/10.1002/humu.23902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953250PMC
January 2020

Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy.

Am J Med Genet A 2019 08 17;179(8):1543-1546. Epub 2019 Jun 17.

Stanford University, Stanford, California.

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.
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http://dx.doi.org/10.1002/ajmg.a.61266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254578PMC
August 2019

Mutation update for the SATB2 gene.

Hum Mutat 2019 08 18;40(8):1013-1029. Epub 2019 Jun 18.

Department of Genetics, Cook Chldren's Medical Center, Fort Worth, Texas.

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.
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http://dx.doi.org/10.1002/humu.23771DOI Listing
August 2019

Acute leukemia in a patient with 15q overgrowth syndrome.

Am J Med Genet A 2019 06 12;179(6):1025-1029. Epub 2019 Mar 12.

Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, California.

Overgrowth syndromes are rare genetic conditions which present as global or segmental hyperplasia and are sometimes associated with increased risk of malignancy. Trisomy of the terminal portion of 15q which includes the IGFR1 gene, produces a rare overgrowth phenotype that has been termed 15q overgrowth syndrome (15q OGS). Upregulation of IGF1R has long been implicated in oncogenesis of multiple cancer types, including acute leukemias, and has been shown to render cells more susceptible to other transforming events. To date, too few cases of 15q OGS have been reported to identify any cancer predisposition. We present a case of a 34-year-old female with intellectual disability, macrocephaly, and subtle dysmorphic features who was diagnosed with mixed phenotype acute leukemia (lymphoid and myeloid). Prior to initiation of therapy she was referred to medical genetics for further evaluation and was identified as having a chromosomal translocation resulting in a partial trisomy of chromosome 15q, consistent with 15q OGS. A review of the literature for cases of malignancy in individuals with increased copy number of 15q revealed only one other reported patient. Given the small number of reported individuals, we cannot rule out an increased risk of cancer associated with this chromosomal overgrowth syndrome. Although concerns have been raised regarding treatment feasibility in the setting of chromosomal disorders, the reported patient underwent successful treatment with allogeneic hematopoietic stem-cell transplant.
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http://dx.doi.org/10.1002/ajmg.a.61115DOI Listing
June 2019

Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy.

Am J Hum Genet 2018 11 25;103(5):817-825. Epub 2018 Oct 25.

Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.

ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218634PMC
November 2018

Prevalence of Fetal Alcohol Spectrum Disorders in 4 US Communities.

JAMA 2018 02;319(5):474-482

University of Arizona College of Medicine, Tucson.

Importance: Fetal alcohol spectrum disorders are costly, life-long disabilities. Older data suggested the prevalence of the disorder in the United States was 10 per 1000 children; however, there are few current estimates based on larger, diverse US population samples.

Objective: To estimate the prevalence of fetal alcohol spectrum disorders, including fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder, in 4 regions of the United States.

Design, Setting, And Participants: Active case ascertainment methods using a cross-sectional design were used to assess children for fetal alcohol spectrum disorders between 2010 and 2016. Children were systematically assessed in the 4 domains that contribute to the fetal alcohol spectrum disorder continuum: dysmorphic features, physical growth, neurobehavioral development, and prenatal alcohol exposure. The settings were 4 communities in the Rocky Mountain, Midwestern, Southeastern, and Pacific Southwestern regions of the United States. First-grade children and their parents or guardians were enrolled.

Exposures: Alcohol consumption during pregnancy.

Main Outcomes And Measures: Prevalence of fetal alcohol spectrum disorders in the 4 communities was the main outcome. Conservative estimates for the prevalence of the disorder and 95% CIs were calculated using the eligible first-grade population as the denominator. Weighted prevalences and 95% CIs were also estimated, accounting for the sampling schemes and using data restricted to children who received a full evaluation.

Results: A total of 6639 children were selected for participation from a population of 13 146 first-graders (boys, 51.9%; mean age, 6.7 years [SD, 0.41] and white maternal race, 79.3%). A total of 222 cases of fetal alcohol spectrum disorders were identified. The conservative prevalence estimates for fetal alcohol spectrum disorders ranged from 11.3 (95% CI, 7.8-15.8) to 50.0 (95% CI, 39.9-61.7) per 1000 children. The weighted prevalence estimates for fetal alcohol spectrum disorders ranged from 31.1 (95% CI, 16.1-54.0) to 98.5 (95% CI, 57.5-139.5) per 1000 children.

Conclusions And Relevance: Estimated prevalence of fetal alcohol spectrum disorders among first-graders in 4 US communities ranged from 1.1% to 5.0% using a conservative approach. These findings may represent more accurate US prevalence estimates than previous studies but may not be generalizable to all communities.
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http://dx.doi.org/10.1001/jama.2017.21896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839298PMC
February 2018

Who is most affected by prenatal alcohol exposure: Boys or girls?

Drug Alcohol Depend 2017 08 15;177:258-267. Epub 2017 Jun 15.

Sanford Research, University of South Dakota Sanford School of Medicine, Department of Pediatrics, United States; University of Arizona, Department of Pediatrics, United States.

Objective: To examine outcomes among boys and girls that are associated with prenatal alcohol exposure.

Methods: Boys and girls with fetal alcohol spectrum disorders (FASD) and randomly-selected controls were compared on a variety of physical and neurobehavioral traits.

Results: Sex ratios indicated that heavy maternal binge drinking may have significantly diminished viability to birth and survival of boys postpartum more than girls by age seven. Case control comparisons of a variety of physical and neurobehavioral traits at age seven indicate that both sexes were affected similarly for a majority of variables. However, alcohol-exposed girls had significantly more dysmorphology overall than boys and performed significantly worse on non-verbal IQ tests than males. A three-step sequential regression analysis, controlling for multiple covariates, further indicated that dysmorphology among girls was significantly more associated with five maternal drinking variables and three distal maternal risk factors. However, the overall model, which included five associated neurobehavioral measures at step three, was not significant (p=0.09, two-tailed test). A separate sequential logistic regression analysis of predictors of a FASD diagnosis, however, indicated significantly more negative outcomes overall for girls than boys (Nagelkerke R=0.42 for boys and 0.54 for girls, z=-2.9, p=0.004).

Conclusion: Boys and girls had mostly similar outcomes when prenatal alcohol exposure was linked to poor physical and neurocognitive development. Nevertheless, sex ratios implicate lower viability and survival of males by first grade, and girls have more dysmorphology and neurocognitive impairment than boys resulting in a higher probability of a FASD diagnosis.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.04.010DOI Listing
August 2017

Replication of High Fetal Alcohol Spectrum Disorders Prevalence Rates, Child Characteristics, and Maternal Risk Factors in a Second Sample of Rural Communities in South Africa.

Int J Environ Res Public Health 2017 05 12;14(5). Epub 2017 May 12.

Department of Pediatrics, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA.

: Prevalence and characteristics of fetal alcohol syndrome (FAS) and total fetal alcohol spectrum disorders (FASD) were studied in a second sample of three South African rural communities to assess change. : Active case ascertainment focused on children with height, weight and/or head circumference ≤25th centile and randomly-selected children. Final diagnoses were based on dysmorphology, neurobehavioral scores, and maternal risk interviews. : Cardinal facial features, head circumference, and total dysmorphology scores differentiated specific FASD diagnostic categories in a somewhat linear fashion but all FASD traits were significantly worse than those of randomly-selected controls. Neurodevelopmental delays were significantly worse for children with FASD than controls. Binge alcohol use was clearly documented as the proximal maternal risk factor for FASD, and significant distal risk factors were: low body mass, education, and income; high gravidity, parity, and age at birth of the index child. FAS rates continue to extremely high in these communities at 9-129 per 1000 children. Total FASD affect 196-276 per 1000 or 20-28% of the children in these communities. : Very high rates of FASD persist in these general populations where regular, heavy drinking, often in a binge fashion, co-occurs with low socioeconomic conditions.
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http://dx.doi.org/10.3390/ijerph14050522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451973PMC
May 2017

Exome sequencing identifies de novo pathogenic variants in and in a patient with a complex connective tissue phenotype.

Cold Spring Harb Mol Case Stud 2017 Jan;3(1):a001388

Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California 94305, USA.

Here we describe a patient who presented with a history of congenital diaphragmatic hernia, inguinal hernia, and recurrent umbilical hernia. She also has joint laxity, hypotonia, and dysmorphic features. A unifying diagnosis was not identified based on her clinical phenotype. As part of her evaluation through the Undiagnosed Diseases Network, trio whole-exome sequencing was performed. Pathogenic variants in and were identified as causing two distinct autosomal dominant conditions, each with de novo inheritance. Fibrillin 1 ( mutations are associated with Marfan syndrome and a spectrum of similar phenotypes. mutations are associated with trichorhinophalangeal syndrome types I and III. Features of both conditions are evident in the patient reported here. Discrepant features of the conditions (e.g., stature) and the young age of the patient may have made a clinical diagnosis more difficult in the absence of exome-wide genetic testing.
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http://dx.doi.org/10.1101/mcs.a001388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171698PMC
January 2017

The continuum of fetal alcohol spectrum disorders in a community in South Africa: Prevalence and characteristics in a fifth sample.

Drug Alcohol Depend 2016 Nov 6;168:274-286. Epub 2016 Oct 6.

Sanford Research, University of South Dakota Sanford School of Medicine, Department of Pediatrics, United States; The University of Arizona College of Medicine, Department of Pediatrics and the Center for Applied Genetics and Genomic Medicine, United States.

Background: The prevalence and characteristics of the continuum of diagnoses within fetal alcohol spectrum disorders (FASD) were researched in a fifth sample in a South African community.

Methods: An active case ascertainment approach was employed among all first grade learners in this community (n=862). Following individual examination by clinical geneticists/dysmorphologists, cognitive/behavioral testing, and maternal interviews, final diagnoses were made in multidisciplinary case conferences.

Results: Physical measurements, cardinal facial features of FAS, and total dysmorphology scores clearly differentiated diagnostic categories in a consistent, linear fashion, from severe to mild. Neurodevelopmental delays and behavioral problems were significantly worse for each of the FASD diagnostic categories, although not as consistently linear across diagnostic groups. Alcohol use was documented by direct report from the mother in 71% to 100% of cases in specific diagnostic groups. Significant distal maternal risk factors in this population are: advanced maternal age at pregnancy; low height, weight, and body mass index (BMI); small head circumference; low education; low income; and rural residence. Even when controlling for socioeconomic status, prenatal drinking correlates significantly with total dysmorphology score, head circumference, and five cognitive and behavioral measures. In this community, FAS occurs in 59-79 per 1,000 children, and total FASD in 170-233 per 1,000 children, or 17% to 23%.

Conclusions: Very high rates of FASD continue in this community where entrenched practices of regular binge drinking co-exist with challenging conditions for childbearing and child development in a significant portion of the population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086258PMC
http://dx.doi.org/10.1016/j.drugalcdep.2016.09.025DOI Listing
November 2016

Analysis of in pediatric and adult glaucoma and other ocular phenotypes.

Mol Vis 2016 17;22:1229-1238. Epub 2016 Oct 17.

Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI; Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI.

Purpose: The gene encodes an enzyme that is a member of the cytochrome P450 superfamily. Mutations in have been mainly reported in recessive pediatric ocular phenotypes, such as primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD), with some likely pathogenic variants also identified in families affected with adult-onset primary open angle glaucoma (POAG).

Methods: We examined in 158 pediatric patients affected with PCG (eight), CG with ASD (22), CG with other developmental ocular disorders (11), juvenile glaucoma with or without additional ocular anomalies (26), and ASD or other developmental ocular conditions without glaucoma (91); in addition, a large cohort of adult patients with POAG (193) and POAG-negative controls (288) was examined.

Results: Recessive pathogenic variants in were identified in two PCG pedigrees, three cases with CG and ASD, and two families with CG and other ocular defects, such as sclerocornea in one patient and microphthalmia in another individual; neither sclerocornea nor microphthalmia has been previously associated with . Most of the identified causative mutations are new occurrences of previously reported pathogenic alleles with two novel variants identified: a c.1325delC, p.(Pro442Glnfs*15) frameshift allele in a family with PCG and a c.157G>A, p.(Gly53Ser) variant identified in a proband with CG, Peters anomaly, and microphthalmia. Analysis of the family history in the -positive families revealed POAG in confirmed or presumed heterozygous relatives in one family with PCG and two families with ASD/CG; POAG was associated with the c.1064_1076del, p.(Arg355Hisfs*69) allele in two of these pedigrees. Screening of an unrelated POAG cohort identified the same c.1064_1076del heterozygous allele in one individual with sporadic POAG but not in age- and ethnicity-matched POAG-negative individuals. Overall, there was no significant enrichment for mutant alleles in within the POAG cases compared to the controls.

Conclusions: In summary, these data expand the mutational and phenotypic spectra of to include two novel alleles and additional developmental ocular phenotypes. The contribution of to POAG is less clear, but loss-of-function variants in , especially c.1064_1076del, p.(Arg355Hisfs*69), may be associated with an increased risk for POAG.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070572PMC
January 2018

Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders.

Pediatrics 2016 08 27;138(2). Epub 2016 Jul 27.

Sanford Research and Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota; Center on Alcoholism, Substance Abuse and Addictions, University of New Mexico, Albuquerque, New Mexico; Department of Nutrition, Gillings School of Global Public Health, Nutrition Research Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors' combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism-funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol.
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http://dx.doi.org/10.1542/peds.2015-4256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960726PMC
August 2016

Breastfeeding and maternal alcohol use: Prevalence and effects on child outcomes and fetal alcohol spectrum disorders.

Reprod Toxicol 2016 08 10;63:13-21. Epub 2016 May 10.

Stellenbosch University, Faculty of Medicine and Health Sciences, South Africa.

Objective: Determine any effects that maternal alcohol consumption during the breastfeeding period has on child outcomes.

Methods: Population-based samples of children with fetal alcohol spectrum disorders (FASD), normally-developing children, and their mothers were analyzed for differences in child outcomes.

Results: Ninety percent (90%) of mothers breastfed for an average of 19.9 months. Of mothers who drank postpartum and breastfed (MDPB), 47% breastfed for 12 months or more. In case control analyses, children of MDPB were significantly lighter, had lower verbal IQ scores, and more anomalies in comparisons controlling for prenatal alcohol exposure and final FASD diagnosis. Utilizing a stepwise logistic regression model adjusting for nine confounders of prenatal drinking and other maternal risks, MDPB were 6.4 times more likely to have a child with FASD than breastfeeding mothers who abstained from alcohol while breastfeeding.

Conclusions: Alcohol use during the period of breastfeeding was found to significantly compromise a child's development.
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http://dx.doi.org/10.1016/j.reprotox.2016.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987236PMC
August 2016

The continuum of fetal alcohol spectrum disorders in four rural communities in South Africa: Prevalence and characteristics.

Drug Alcohol Depend 2016 Feb 31;159:207-18. Epub 2015 Dec 31.

Sanford Research, University of South Dakota Sanford School of Medicine, Department of Pediatrics, United States.

Background: Prevalence and characteristics of the continuum of diagnoses within fetal alcohol spectrum disorders (FASD) were researched in previously unstudied rural, agricultural, lower socioeconomic populations in South Africa (ZA).

Methods: Using an active case ascertainment approach among first grade learners, 1354 (72.6%) were consented into the study via: height, weight, and/or head circumference ≤ 25th centile and/or random selection as normal control candidates. Final diagnoses were made following: examination by pediatric dysmorphologists/geneticists, cognitive/behavioral testing, and maternal risk factor interviews.

Results: FASD children were significantly growth deficient and dysmorphic: physical measurements, cardinal facial features of FAS, and total dysmorphology scores clearly differentiated diagnostic categories from severe to mild to normal in a consistent, linear fashion. Neurodevelopmental delays were also significantly worse for each of the FASD diagnostic categories, although not as consistently linear across groups. Alcohol use is well documented as the proximal maternal risk factor for each diagnostic group. Significant distal maternal risk factors in this population are: low body weight, body mass, education, and income; and high gravidity, parity, and age at birth of the index child. In this low SES, highly rural region, FAS occurs in 93-128 per 1000 children, PFAS in 58-86, and, ARND in 32-46 per 1000. Total FASD affect 182-259 per 1000 children or 18-26%.

Conclusions: Very high rates of FASD exist in these rural areas and isolated towns where entrenched practices of regular binge drinking co-exist with challenging conditions for childbearing and child development.
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http://dx.doi.org/10.1016/j.drugalcdep.2015.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724497PMC
February 2016

De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay.

Am J Hum Genet 2015 Mar 26;96(3):498-506. Epub 2015 Feb 26.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129∗]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024∗]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.
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http://dx.doi.org/10.1016/j.ajhg.2015.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375619PMC
March 2015

Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation.

Am J Med Genet A 2015 Apr 23;167A(4):882-5. Epub 2015 Feb 23.

Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California.

Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation.
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http://dx.doi.org/10.1002/ajmg.a.37024DOI Listing
April 2015
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