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There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

Perinatal death, of a fetus or newborn, is a devastating event for families. Following nationwide multicentre recruitment, we assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who experienced perinatal death, and provided a definite or candidate genetic diagnosis in 105 families. From this understudied cohort, half of the (candidate) diagnoses were phenotype expansions or novel disease genes, revealing previously unknown in-utero presentations of existing developmental disorders, and genomic disorders that are likely incompatible with life. Among the definite diagnoses, 43% were recessively or dominantly inherited, posing a 25% or 50% recurrence risk for future pregnancies. Ten families used their diagnosis for preimplantation or prenatal diagnosis of 12 pregnancies, facilitating the delivery of ten healthy newborns and management of two affected pregnancies. We emphasize the clinical importance of genomic investigations of perinatal death, with short turn-around times, enabling accurate counselling and options for families to prevent recurrence.

BACKGROUND AND PURPOSE: Ganglionic eminence abnormalities on fetal MR imaging are associated with cerebral malformations. Their presumed genetic basis and associated postnatal outcomes remain largely unknown. We aimed to elucidate these through a multicenter study. MATERIALS AND METHODS: Between January 2010 and June 2020, seven hospitals in 2 countries performing fetal MR imaging examinations identified fetal MR imaging studies demonstrating ganglionic eminence enlargement, cavitation, or both. Cases with no genetic diagnosis, no whole exome sequencing, or no outcome of a liveborn child were excluded. Head size was classified as large (fronto-occipital diameter > 95th centile), small (fronto-occipital diameter

Purpose: To explore parental experiences of ultrarapid genomic testing for their critically unwell infants and children. Methods: Parents of critically unwell children who participated in a national ultrarapid genomic diagnosis program were surveyed >12 weeks after genomic results return. Surveys consisted of custom questions and validated scales, including the Decision Regret Scale and Genomics Outcome Scale. Results: With 96 survey invitations sent, the response rate was 57% (n = 55). Most parents reported receiving enough information during pretest (n = 50, 94%) and post-test (n = 44, 83%) counseling. Perceptions varied regarding benefits of testing, however most parents reported no or mild decision regret (n = 45, 82%). The majority of parents (31/52, 60%) were extremely concerned about the condition recurring in future children, regardless of actual or perceived recurrence risk. Parents whose child received a diagnostic result reported higher empowerment. Conclusion: This study provides valuable insight into parental experiences of ultrarapid genomic testing in critically unwell children, including decision regret, empowerment, and post-test reproductive planning, to inform design and delivery of rapid diagnosis programs. The findings suggest considerations for pre- and post-test counseling that may influence parental experiences during the testing process and beyond, such as the importance of realistically conveying the likelihood for clinical and/or personal utility. Refereed/Peer-reviewed

Objective The aim of this study was to (1) examine the psychological impact of non-invasive prenatal testing (NIPT) in women with a high-risk (≥1:300) and low-risk (≤1:301) result on combined First Trimester Screening (cFTS); and (2) to examine factors influencing anxiety and decision-making in both risk populations. Method Questionnaires and structured interviews were administered to low (n = 50) and high (n =63) risk women at the time of NIPT blood draw (point A) and again at least one week after receiving their NIPT result (point B). Anxiety levels were measured at these two time points using the State-Trait Anxiety Inventory (STAI). Results Both high and low risk cFTS groups demonstrated similar intrinsic (trait) anxiety levels (36+10 vs. 35+10; p=0.70). High risk women had significantly higher levels of state anxiety at point A than low risk women (42+11 vs. 36+11; p

Multiple studies have shown that genomic testing has a high diagnostic yield and an impact on clinical management for patients with suspected genetic conditions. Therefore, there has been a push worldwide to apply rapid genomic sequencing in critically ill neonatal and pediatric patients. The goal of this study was to investigate the practicality of applying ultrarapid genomic testing for critically ill neonatal and pediatric patients with suspected monogenic conditions in Australia. The study recruited a total of 108 patients prospectively from March 2018 to February 2019, and data were collected until May 2019. Of the 12 hospitals that acted as collaborating sites, 5 were women's hospitals, 3 women's and children's hospitals, and 4 children's hospitals. Eligible patients included those who were admitted to a neonatal or pediatric intensive care unit (NICU or PICU) and were referred to clinical genetics for a possible monogenic condition. Chromosomal microarray was a requirement before enrollment if there was a suspected chromosomal condition. Chromosomal microarrays were performed concurrently with ultrarapid exome sequencing when the probability of a positive result on microarray was low. Additionally, rapid mitochondrial genome sequencing was performed alongside ultrarapid exome sequencing if a mitochondrial condition was suspected. When possible, ultrarapid exome sequencing was performed in both parents as well as the child (trio). The primary outcome of this study measured the time from the last sample received to the ultrarapid exome sequencing report finalized. Other outcomes measured were the diagnostic yield, change in clinical management after the report was finalized, number of reports returned before hospital discharge, and time from admission to the report being finalized. Of the 108 patients enrolled, the median age was 28 days, with a range of 0 days to 17 years. Overall, 34% were female, 57% were NICU admissions, 33% were PICU admissions, and 9% were from other hospital wards. The mean time it took from the last sample received to the report being issued was 3.3 days (95% confidence interval [CI], 3.2-3.5 days). The mean time from hospital admission to the sequencing report being finalized was 17.5 days (95% CI, 14.6-21.1 days). The mean time from hospital admission to clinical genetics referral was 8.1 days (95% CI, 6.0-10.8 days). Overall, 94% of reports were issued within the goal of 5 calendar days, and 56 molecular diagnoses were made for 55 patients (51%). Among the 62 patients in the NICU, 35 had a clear molecular diagnosis from ultrarapid exome sequencing (56%), whereas in the 36 PICU patients, 17 had a clear molecular diagnosis (47%), and in the 10 patients from other hospital wards, 3 had a clear molecular diagnosis (30%). After the ultrarapid exome sequencing report was finalized, clinical management changed for 48 of the 108 patients enrolled (44%). Overall, the ultrarapid sequencing reports that revealed a clear molecular diagnosis were regarded as “very useful” or “useful” by referring providers in 52 of 55 cases (95%) and “neutral” in 3 of 55 cases (5%). Negative reports were regarded as “very useful” or “useful” in 31 of 53 cases (58%), “neutral” in 20 of 53 cases, and “not useful” in 2 of 53 cases (4%). Altogether, this study demonstrates the utility of ultrarapid exome sequencing in critically ill pediatric patients with a suspected monogenic condition in Australia. Refereed/Peer-reviewed

We investigated the attitudes of intensive care physicians and genetics professionals towards rapid genomic testing in neonatal and paediatric intensive care units (NICU/PICU). A mixed-methods study (surveys and interviews) was conducted at 13 Australian hospitals and three laboratories involved in multi-center implementation of rapid genomic testing. We investigated experience and confidence with genomic tests among intensivists; perceived usefulness of genomic diagnostic results; preferences for service delivery models; and implementation readiness among genetic services. The overall survey response rate was 59%, 47% for intensivists (80/170), and 75% (91/121) for genetics professionals. Intensivists reported moderate confidence with microarray tests and lower confidence with genomic tests. The majority of intensivists (77%), clinical geneticists (87%) and genetic counsellors (82%) favoured a clinical genetics-led service delivery model of genomic testing. Perceived clinical utility of genomic results was lower in the intensivist group compared to the genetics professionals group (20 v 50%, p

Mowat-Wilson syndrome (MWS) is a complex genetic disorder associated with heterozygous variation in ZEB2. It is mainly characterized by moderate-to-severe intellectual disability, facial dysmorphism, epilepsy, and various malformations including Hirschsprung disease, corpus callosum anomalies, and congenital heart defects. It is rarely diagnosed prenatally and there is limited information available on the prenatal phenotype associated with MWS. Here we report the detection of a heterozygous de novo nonsense variant in ZEB2 by whole exome sequencing in a fetus with microphthalmia in addition to cardiac defects and typical MWS facial dysmorphism. As the prenatal phenotypic spectrum of MWS expands, the routine addition of fetal genomic testing particularly in the presence of multiple malformations will increase both the sensitivity and specificity of prenatal diagnostics.

Background Miller syndrome (post-axial acrofacial dysostosis) arises from gene mutations for the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Nonetheless, despite demonstrated loss of enzyme activity dihydroorotate (DHO) has not been shown to accumulate, but paradoxically urine orotate has been reported to be raised, confusing the metabolic diagnosis. Methods We analysed plasma and urine from a 4-year-old male Miller syndrome patient. DHODH mutations were determined by PCR and Sanger sequencing. Analysis of DHO and orotic acid (OA) in urine, plasma and blood-spot cards was performed using liquid chromatography-tandem mass spectrometry. In vitro stability of DHO in distilled water and control urine was assessed for up to 60h. The patient received a 3-month trial of oral uridine for behavioural problems. Results The patient had early liver complications that are atypical of Miller syndrome. DHODH genotyping demonstrated compound-heterozygosity for frameshift and missense mutations. DHO was grossly raised in urine and plasma, and was detectable in dried spots of blood and plasma. OA was raised in urine but undetectable in plasma. DHO did not spontaneously degrade to OA. Uridine therapy did not appear to resolve behavioural problems during treatment, but it lowered plasma DHO. Conclusion This case with grossly raised plasma DHO represents the first biochemical confirmation of functional DHODH deficiency. DHO was also easily detectable in dried plasma and blood spots. We concluded that DHO oxidation to OA must occur enzymatically during renal secretion. This case resolved the biochemical conundrum in previous reports of Miller syndrome patients, and opened the possibility of rapid biochemical screening.

IMPORTANCE: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.OBJECTIVE: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.DESIGN, SETTING, AND PARTICIPANTS: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination,distributed leadership, and collective learning was used to facilitate adoption.EXPOSURES Ultra-rapid exome sequencing.MAIN OUTCOMES AND MEASURES: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge RESULTS: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The meantime from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI,3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing–based copy number analysis, use of international databases to identify novel gene–disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%)without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients(11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%).CONCLUSIONS AND RELEVANCE: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings. Refereed/Peer-reviewed

A 24-year-old white European woman with diet-treated diabetes since 15 years of age presented prior to her first pregnancy. Her prepregnancy HbA1c was 5.8% (40 mmol/mol), and HbA1c at 12 weeks’ gestation was 6.0% (42 mmol/mol). She received insulin therapy from 13 weeks (up to 0.3 units/kg/day) and had a vaginal delivery of a boy weighing 3,205 g (84th centile) at 37 weeks. He had neonatal jaundice and bilateral vesicoureteral reflux requiring reimplantation surgery (Table 1). View this table: Table 1 Details of GCK-MODY pregnancies in this case report Her second pregnancy was managed similarly, with insulin therapy from 4 weeks’ gestation (up to 0.7 units/kg/day). The HbA1c was 5.5% (37 mmol/mol) at 8 weeks. She had a vaginal delivery of a healthy girl weighing 3,235 g (33rd centile) following induction of labor at 40 weeks. Postpartum, the mother’s persistent fasting hyperglycemia, small increment on a 75-g oral glucose tolerance test (6.2, 7.7, and 6.3 mmol/L [fasting, 1 h, and 2 h, respectively]), and two-generation family history of diabetes suggested glucokinase–maturity-onset diabetes of the young (GCK-MODY), which was confirmed on genetic testing (heterozygous glucokinase ( GCK ) mutation c.952G>A, p.Gly318Arg). Her third pregnancy …

Contains fulltext : 168023.pdf (Publisher’s version ) (Closed access) Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

OBJECTIVE Glucokinase monogenic diabetes (GCK–maturity-onset diabetes of the young [MODY]) should be differentiated from gestational diabetes mellitus (GDM) because management differs. New pregnancy-specific screening criteria (NSC) have been proposed to identify women who warrant GCK genetic testing. We tested NSC and HbA1c in a multiethnic GDM cohort and examined projected referrals for GCK testing. RESEARCH DESIGN AND METHODS Using a GDM database, 63 of 776 women had a postpartum oral glucose tolerance test suggestive of GCK-MODY. Of these 63 women, 31 agreed to undergo GCK testing. NSC accuracy and HbA1c were examined. Projected referrals were calculated by applying the NSC to a larger GDM database (n = 4,415). RESULTS Four of 31 women were confirmed as having GCK-MODY (prevalence ∼0.5–1/100 with GDM). The NSC identified all Anglo-Celtic women but did not identify one Indian woman. The NSC will refer 6.1% of GDM cases for GCK testing, with more Asian/Indian women referred despite lower disease prevalence. Antepartum HbA1c was not higher in those with GCK-MODY. CONCLUSIONS The NSC performed well in Anglo-Celtic women. Ethnic-specific criteria should be explored.

Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ∼50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ∼70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.

The aim of this study was to (1) examine the psychological impact of non-invasive prenatal testing (NIPT) in women with a high-risk (≥1 : 300) and low-risk (≤1 : 301) result on combined first trimester screening (cFTS) and (2) to examine factors influencing anxiety and decision-making in both risk populations.Questionnaires and structured interviews were administered to low (n = 50) and high (n = 63) risk women at the time of NIPT blood draw (point A) and again at least 1 week after receiving their NIPT result (point B). Anxiety levels were measured at these two time points using the State-Trait Anxiety Inventory.Both high-risk and low-risk cFTS groups demonstrated similar intrinsic (trait) anxiety levels (36 ± 10 vs 35 ± 10; p = 0.70). High-risk women had significantly higher levels of state anxiety at point A than low-risk women (42 ± 11 vs 36 ± 11; p 0.01). Both groups had a statistically significant reduction (p 0.01), to similar final levels of state anxiety at point B (30 ± 11 vs 29 ± 8; p = 0.61).Women receiving a high-risk result on cFTS have higher levels of state anxiety than their low-risk counterparts. Following a low-risk NIPT result, the anxiety levels in both populations are reduced to similar levels. © 2017 John WileySons, Ltd.

Background: Asparagine Synthetase Deficiency (ASNSD; OMIM #615574) is a newly described rare autosomal recessive neurometabolic disorder, characterised by congenital microcephaly, severe psychomotor delay, encephalopathy and progressive cerebral atrophy. To date, seven families and seven missense mutations in the ASNSD disease causing gene, ASNS, have been published. Methods: We report two further affected infant sisters from a consanguineous Indian family, who in addition to the previously described features had diaphragmatic eventration. Both girls died within the first 6 months of life. Whole exome sequencing (WES) was performed for both sisters to identify the pathogenic mutation. The clinical and biochemical parameters of our patient are compared to previous reports. Results: WES demonstrated a homozygous novel missense ASNS mutation, c.1019G > A, resulting in substitution of the highly conserved arginine residue by histidine (R340H). Conclusion: This report expands the phenotypic and mutation spectrum of ASNSD, which should be considered in neonates with congenital microcephaly, seizures and profound neurodevelopmental delay. The presence of diaphragmatic eventration suggests extracranial involvement of the central nervous system in a disorder that was previously thought to exclusively affect the brain. Like all previously reported patients, these cases were diagnosed with WES, highlighting the clinical utility of next generation sequencing in the diagnosis of rare, difficult to recognise disorders.

Cavernous haemangiomas of the central nervous system are vascular malformations best imaged by MRI. They may present at any age, but to our knowledge only 39 cases in the first year of life have previously been reported. A familial form has been described and some of the underlying genetic mutations have recently been discovered. We present the clinical features and serial MRI findings of an 8-week-old boy who presented with subacute intracranial haemorrhage followed by rapid growth of a surgically proven cavernous haemangioma, mimicking a tumour. He also developed new lesions. A strong family history of neurological disease was elucidated. A familial form of cavernous haemangioma was confirmed by identification of a KRIT 1 gene mutation and cavernous haemangiomas in the patient and other family members. We stress the importance of considering cavernous haemangiomas in the context of intracerebral haemorrhage and in the differential diagnosis of rapidly growing lesions in this age group. The family history is also important in screening for familial disease.

OBJECTIVE. The purpose of this research was to assess the effects of breast milk on the severity and outcome of neonatal abstinence syndrome.METHODS. We conducted a retrospective chart review of 190 drug-dependent mother and infant pairs. Patients were categorized according to the predominant type of milk consumed by the infant on the fifth day of life (breast milk: n = 85 or formula: n = 105). The Finnegan's scoring system was used to monitor withdrawal, and medication was commenced if there were 2 scores of ≥8.RESULTS. Mean Finnegan scores were significantly lower in the breast milk group during the first 9 days of life even after stratifying for prematurity and exposure to polydrug and methadone. Significantly fewer infants required withdrawal treatment in the breast milk group. The median time to withdrawal occurred considerably later in breast milk group. In a multivariate analysis controlled for exposure to drugs of high risk of neonatal abstinence syndrome, polydrug, and prematurity, breast milk group was associated with lower need for neonatal abstinence syndrome treatment.CONCLUSIONS. Breast milk intake is associated with reduced neonatal abstinence syndrome severity, delayed onset of neonatal abstinence syndrome, and decreased need for pharmacologic treatment, regardless of the gestation and the type of drug exposure.

OBJECTIVE In women with hyperglycemia due to heterozygous glucokinase (GCK) mutations, the fetal genotype determines its growth. If the fetus inherits the mutation, birth weight is normal when maternal hyperglycemia is not treated, whereas intensive treatment may adversely reduce fetal growth. However, fetal genotype is not usually known antenatally, making treatment decisions difficult. HISTORY AND EXAMINATION We report two women with gestational diabetes mellitus resulting from GCK mutations with hyperglycemia sufficient to merit treatment. INVESTIGATION In both women, DNA from chorionic villus sampling, performed after high-risk aneuploidy screening, showed the fetus had inherited the GCK mutation. Therefore, maternal hyperglycemia was not treated. Both offspring had a normal birth weight and no peripartum complications. CONCLUSIONS In pregnancies where the mother has hyperglycemia due to a GCK mutation, knowing the fetal GCK genotype guides the management of maternal hyperglycemia. Fetal genotyping should be performed when fetal DNA is available from invasive prenatal diagnostic testing.

Introduction Ornithine transcarbamylase deficiency is the most common hereditary urea cycle defect. It is inherited in an X-linked manner and classically presents in neonates with encephalopathy and hyperammonemia in males. Females and males with hypomorphic mutations present later, sometimes in adulthood, with episodes that are frequently fatal. Case presentation A 13-year-old Caucasian girl presented with progressive encephalopathy, hyperammonemic coma and lactic acidosis. She had a history of intermittent regular episodes of nausea and vomiting from seven years of age, previously diagnosed as abdominal migraines. At presentation she was hyperammonemic (ammonia 477 μmol/L) with no other biochemical indicators of hepatic dysfunction or damage and had grossly elevated urinary orotate (orotate/creatinine ratio 1.866 μmol/mmol creatinine, reference range A) mutation was identified in the ornithine transcarbamylase gene (OTC) in our patient confirming the first symptomatic female shown heterozygous for the R40H mutation. A review of the literature and correspondence with authors of patients with the R40H mutation identified one other symptomatic female patient who died of hyperammonemic coma in her late teens. Conclusions This report expands the clinical spectrum of presentation of ornithine transcarbamylase deficiency to female heterozygotes for the hypomorphic R40H OTC mutation. Although this mutation is usually associated with a mild phenotype, females with this mutation can present with acute decompensation, which can be fatal. Ornithine transcarbamylase deficiency should be considered in the differential diagnosis of unexplained acute confusion, even without a suggestive family history.

We performed haplotype analysis using nine single nucleotide polymorphisms in the ornithine transcarbamylase gene to explore the ancestral origins of three mutations associated with late-onset phenotype in male patients: p.R40H, p.R277W and p.Y55D. Overall, 8 haplotypes were defined among 14 families carrying p.R40H, 5 families carrying p.R277W and 2 families with p.Y55D mutations. Of nine Japanese families carrying p.R40H, eight exhibited haplotype (HT)1, whereas the other family harbored HT2. Among three Caucasian families, one Spanish and one Australian family bore HT3; one Austrian family had HT4. Two US patients harbored HT2 and HT4. Among families carrying p.R277W, HT5 was found in one Japanese, one Korean and one US family. Two other US families had HT2 and HT6. Two families carrying p.Y55D, both Japanese, shared HT1. These results indicate that the p.R40H mutation has arisen recurrently in all populations studied, although there is evidence for a founder effect in Japan, with most cases probably sharing a common origin, and to a lesser extent in subjects of European ancestry (HT3). It is evident that p.R277W mutation has recurred in discrete populations. The p.Y55D mutation appears to have arisen from a common ancestor, because this transversion (c.163T>G) occurs rarely.

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.