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ObjectivesCharacterization of tissue laxityanddysautonomia symptoms in Ehlers-Danlos syndrome (EDS) uncovered similarities with those of post-infectious SARS-CoV-2 or long COVID19, prompting detailed comparison of their findings and influencing genes.MethodsHolistic assessment of 1261 EDS outpatients for 120 history-physical findings populated a deidentified database that includes 568 patients with 317 variant genes obtained by commercial NextGen sequencing. Findings were compared to 15 of long COVID19 compiled in an extensive review, genes to 104 associated with COVID19 severity in multiple molecular studies.ResultsFifteen symptoms common to Ehlers-Danlos versus long COVID19 ranged from brain fog (27-80 versus 30-70%), chronic fatigue (38-91; 30-60%), dyspnea (32-52; 29-52%) to irritable bowel (67-89; 14-78%), muscle weakness (22-49; 15-25%), and arthritis (32-94; 15-27%). Genes relevant to EDS included 6 identical to those influencing COVID19 severity (F2,LIFR,NLRP3,STAT1,T1CAM1,TNFRSF13B) and 18 similar includingPOLG-POLD4,SLC6A2-SLC6A20, andNFKB1-NFKB2. Both gene sets had broad genomic distribution, many mitochondrial genes influencing EDS and many involved with immunity-inflammation modifying COVID19 severity. Recurring DNA variants in EDS that merit evaluation in COVID19 resistance include those impacting connective tissue elements--51 inCOL5(joint), 29 inCOL1/2/9/11(bone), 13 inCOL3(vessel), and 18 inFBN1(vessel-heart)--or neural function--93 in mitochondrial DNA, 28 inCOL6/12, 16 inSCN9A/10A/11A, 14 inPOLG, and 11 in genes associated with porphyria.ConclusionsHolistic ascertainment of finding pattern and exome variation in EDS defined tissue laxity, neuromuscular, and autonomic correlations that transcend single abnormalities or types. Implied networks of nuclear and mitochondrial genes are linked to findings like brain fog, fatigue, and frailty in EDS, their similarity to long COVID19 supporting shared therapies for disorders affecting a minimum 0.1% of the global population.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and one was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.

Background: Dental complications of Ehlers-Danlos syndrome (EDS) include periodontitis with gum fragility and inflammation, enamel hypoplasia with frequent caries, high palate with dental crowding, TMJ instability, sutural dehiscence or scarring, and insensitivity to anesthetics. Objective: Determine if EDS dental complications always define a specific type and genetic cause or if they can arise as a general consequence of altered inflammatory response in EDS. Method: We compared findings of a 58-year-old female with complement component 1R (C1R) gene mutation (c.1553A > T, p.Asp518Val) found by whole exome sequencing to 43 patients with C1R gene mutations ascertained because of periodontal disease and to 710 EDS patients conventially ascertained because of joint and skin laxity. Result: Female patients ascertained as periodontal EDS showed the expected higher frequency of periodontitis (96% versus 14%) but had similar frequencies of hypermobility (81% versus 90%) and some skin findings (84% versus 92% with skin fragility) as the general group and our female patient who shared their C1R gene change. Her oromandibular bone loss rather than gum disease may reflect the more carboxy-terminal position of her C1R gene mutation compared to those in the patients identified as periodontal EDS. Conclusion: While mutation of the C1R gene may predict more frequent periodontal, skin, and vascular complications, focus on an articulo-autonomic dysplasia process that includes mast-cell activation and altered inflammatory response rather than extreme EDS types will help dentists and other subspecialists identify all EDS patients and anticipate their frequent oral manifestations.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)

A novel medical approach for qualifying DNA variants found by whole exome sequencing (WES) facilitates discovery of new gene-disease relationships and emphasizes that DNA change must be correlated with clinical findings before having utility for diagnosis. Delineation of an arthritis-adrenaline disorder (AAD) process qualified variants in 23 genes as diagnostically useful in 727 patients having WES among 1656 with Ehlers-Danlos syndrome (EDS); these results distinguished them from 102 patients who had qualified gene variants among 728 with developmental disability. Excess maternal transmission of AAD by pedigree analysis plus 167 maternally versus 111 paternally transmitted DNA variants and 75 patients with only mitochondrial DNA variants suggest maternal influence on inheritance of AAD and its subsumed EDS types. Genes grouped by impact on different connective tissue elements showed variation in similar numbers of patients with hypermobile or classical EDS, benign joint hypermobility, or predominant dysautonomia: COL7A1, FLG acting on skin in 21 patients; SCN9A/10A/11A, POLG on nerve in 24; COL6A1/A2/A3, COL12 on muscle in 19; COL5A1/A2, FBN1, TGFB2/3, TGFBR1/2 on tissue matrix in 51; COL3A1, VWF on vessel in 18; COL1A1/A2, COL11A1/A2 acting on bone in 15 patients. Each gene group acts through a postulated articulo-autonomic dysplasia cycle to produce reciprocal tissue laxity and dysautonomia findings that transcend EDS types. This same tissue laxity-dysautonomia cycle acts to produce secondary complications in disorders ranging from distinctive connective tissue dysplasias to developmental disorders with hypotonia and acquired conditions with autonomic imbalance. Several altered genes were previously associated with neuromuscular disorders, foreshadowing a large myopathic EDS category that will incorporate many patients with hypermobility. The importance of muscle for joint constraint supports present exercise and future mesenchymal stem cell therapies, whether AAD is genetic or epigenetic from trauma, surgery, inflammation, or aging.

Findings in 1656 patients referred for evaluation of Ehlers-Danlos syndrome, 710 evaluated systematically using novel history and physical forms, defined a characteristic clinical pattern termed arthritis-adrenaline disorder, a genus that provides immediate therapy while delineation of particular tissue laxity/dysautonomia species is underway. Preliminary diagnoses, clinical findings, and laboratory results were entered into an MS Excel© database with IRB approval and correlations or statistical significance analyzed using Excel© functions. Frequencies of 80 findings by history and 40 on physical were similar among EDS groups, females paralleling males with more total history (35 versus 23) and physical (18 versus 15) findings. Finding frequencies in joint-skeletal (6.2 of 15) and dysautonomia (11 of 20) subcategories were substantial regardless of age, EDS diagnosis, or referral source, the latter was shown by 6.4 and 13 average findings for cardiology, 5.3 and 8.3 for orthopedic referrals. Early affliction evidenced by history findings averaging 19.5 in those under 12 increased dramatically to 25 for teens and 32 for adults with plateauing at older ages arguing against degenerative disease. Frequent neuromuscular symptoms in females emphasize surrounding muscle support and protection of joint-connective tissue as a key factor in decreased male severity. The congruent clinical profile suggests operation of an articulo-autonomic dysplasia cycle where lax vessels and lower body pooling elicit sympathetic response, autonomic imbalance in turn affecting small nerve fibers and enhancing connective tissue laxity. Recognition of this arthritis-adrenalin disorder can guide management strategies while underlying causes are pursued, among them, physical therapy, exercise, and vitamin D to build muscle/bone strength; lower gluten/dairy and antihistamine protocols for low bowel motility/mast-cell activation; hydration, salt, and exercise for postural orthostatic tachycardia syndrome.

Item does not contain fulltext BACKGROUND: Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1 mutations. METHODS: Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards. RESULTS: A mutation in STAG1 was identified in 17 individuals from 16 families, 9 males and 8 females aged 2-33 years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1 deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1 variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy. CONCLUSIONS: We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1 highlights the importance of data sharing in the field of rare disorders.

A female patient with substantial history and physical findings of Ehlers-Danlos syndrome by systematic evaluation had a variant in the gene encoding the sixth subunit of mitochondrial ATP synthetase gene that produced a change from glycine to aspartic acid at position 132 of the MT-ATP6 protein (MT-ATP6 m.8921G>A, p.Gly132Asp). The mutation was heteroplasmic, affecting 32% of the mitochondria in blood leucocytes, was qualified as a pathogenic variant because of its significant molecular change, but was not detected in the maternal blood sample as might be expected for its low degree of heteroplasmy. The patient was shown to have typical findings of Ehlers-Danlos syndrome by comparison of 48 history and physical findings in her and a peer group of 32 teenage females with that diagnosis. None of the classical neurosensory or developmental symptoms of mitochondrial disease were present in mother or daughter, but the patient had symptoms, metabolite alterations during rest or exercise, and muscle biopsy changes that suggested mild mitochondrial dysfunction. She also had heterozygous variants of uncertain significance in the nuclear PLOD1, FLNA, and ATP2A genes by concomitant whole exome sequencing that could also contribute to her arthritis-adrenaline disorder. Mitochondrial dysfunction is proposed to influence neuromuscular components of connective tissue, acting through an articulo-autonomic dysplasia cycle to cause the typical joint-skin laxity and dysautonomia of Ehlers-Danlos syndrome.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Deletions in the middle portion of 11q are not as well described in the literature as terminal 11q deletions that result in Jacobsen syndrome. One confounding factor in the older literature is that the G-banding pattern of 11q13q21 is very similar to 11q21q23. The advent of fluorescence in situ hybridization and later microarray technologies have allowed for a better resolution of many of these deletions, but genotype-phenotype correlations are still difficult since these deletions are rare events. We present five individuals who presented with developmental delays with de novo 11q22.2q23.3 deletions. Deletions were observed by standard G-banded chromosome analysis with clarification of breakpoints and gene content by SNP microarray analysis. Of note, all individuals had identical distal breakpoints. All deletions include SDHD, which is implicated in hereditary paraganglioma/pheochromocytoma, for which the patients will need to be monitored in adulthood. In spite of the large deletions of 8.6 Mb (Patients 1 and 3), 13.98 Mb (Patient 2), and 12.6 Mb (Patients 4 and 5) all patients show somewhat mild intellectual disability and dysmorphism. © 2015 Wiley Periodicals, Inc.

Two revolutionary advances in molecular biology have enabled scanning of the entire human genome for genetic variation: 1. Array-comparative genomic hybridization-microarray analysis (aCGH, CMA, microarray analysis, referred to henceforth as aCGH) that identifies altered DNA dosage. 2. Whole genome or exome sequencing (WGS or WES) that identifies nucleotide sequence changes.

Discussion of DNA diagnosis using targeted DNA or whole exome sequencine (WES) is necessarily truncated because of two reasons.

Rapid incorporation of microarray analysis/aCGH for studies of children with developmental disabilities and its endorsement as a first-tier test for these children [1] has yielded a vast number of subtle chromosome changes that were unseen by routine karyotyping.

Fluorescence in situ hybridization (FISH) has been a powerful adjunct in cytogenetics. In principal, any piece of DNA (or RNA) can be isolated, amplified and labeled.

The following summaries include examples of human chromosome heteromorphisms that have been compiled by us, contributed by individual investigators specifically for this volume, or have been reprinted with permission from various published sources. Individual contributions have been identified by a numerical designation prefixed with the letter “c”, after the name of the contributor, i.e. Lauren Jenkins (c2).

Background/Purpose The increasing prevalence of abdominal wall defects prompted analysis of anomalies associated with gastroschisis and omphalocele in the Texas Birth Defects Registry (TDBR). Methods Cases of gastroschisis (ICD9 code 756.71), omphalocele (756.70), and/or unspecified anomalies of the abdominal wall (756.79) were obtained from the TDBR after IRB approval and analyzed using Microsoft Access© and Excel© databases. Results Analysis began with 2825 cases including 1831 of gastroschisis, 814 of omphalocele, and 180 of unspecified abdominal wall defects plus 9680 associated anomalies that were classified according to system. The overall prevalence of abdominal wall defects among 3,806,299 Texas births from 1999 to 2008 was 7.4 per 10,000 with 4.8 per 10,000 for gastroschisis and 2.1 for omphalocele. After excluding ambiguous cases (8.5% possibly misclassified), anomaly spectra were similar for the two AWD with musculoskeletal (limb contractures or defects), cardiovascular, gastrointestinal, urogenital, and central nervous system defects being most common. Of 1831 cases with gastroschisis, 594 (32%) had associated anomalies compared to 654 (80%) of 814 omphalocele cases. Conclusions Gastroschisis as well as omphalocele has significant associated anomalies that are important to appreciate during pre- and postnatal management.

Patients with KCNK9 imprinting syndrome demonstrate congenital hypotonia, variable cleft palate, normal MRIs and EEGs, delayed development, and feeding problems. Associated facial dysmorphic features include dolichocephaly with bitemporal narrowing, short philtrum, tented upper lip, palatal abnormalities, and small mandible. This disorder maps to chromosomal region 8q24, and it is caused by a specific missense mutation 770G>A in exon 2, replacing glycine at position 236 by arginine (G236R) in the maternal copy of KCNK9 within this locus. KCNK9 (also called TASK3) encodes a member of the two pore- domain potassium channel (K2P) subfamily. This gene is normally imprinted with paternal silencing, thus a mutation in the maternal copy of the gene will result in disease, whereas a mutation in the paternal copy will have no effect. Exome sequencing in four new patients with developmental delay and central hypotonia revealed de novo G236R mutations. Older members of a previously reported Arab-Israeli family have intellectual disability of variable severity, persistent feeding difficulties in infancy with dysphagia of liquids and dysphonia with a muffled voice in early adulthood, generalized hypotonia, weakness of proximal muscles, elongated face with narrow bitemporal diameter, and reduced facial movements. We describe the clinical features in four recently recognized younger patients and compare them with those found in members of the originally reported Arab-Israeli family and suggest this may be a treatable disorder. © 2016 Wiley Periodicals, Inc.

A dilemma of penetrance parallels the uncertainty principle as array analyses uncover a disturbing continuity of human molecular variation. Among mechanisms for altered penetrance is maternal genetic effect, hypothesized to explain mother-offspring discordance from 12/13 translocation [Wilson et al., 1991] and important to consider when confronting identical genetic changes in normal mothers and their abnormal children. A boy with developmental delays, autistic features, minimal dysmorphology, and maternally inherited 17p13.3 microduplication could exemplify maternal genetic effect, as could a boy with altered brain pattern and maternally inherited Sonic Hedgehog mutation reported by Schell-Apacik et al. [2009]. Maternal genetic effects, characterized in fly, fish, and mouse, are important to consider in human DNA analysis so that identical findings in mother and child are not routinely dismissed as benign variations. Suspect families can define relevant maternal-zygote transition (MZT) genes, provide assays for oocyte function and disruption, and shift anomaly emphasis from pattern recognition to pattern restoration. © 2012 Wiley Periodicals, Inc.

Using whole-exome sequencing, we identified seven unrelated individuals with global developmental delay, hypotonia, dysmorphic facial features, and an increased frequency of short stature, ataxia, and autism with de novo heterozygous frameshift, nonsense, splice, and missense variants in the Early B-cell Transcription Factor Family Member 3 (EBF3) gene. EBF3 is a member of the collier/olfactory-1/early B-cell factor (COE) family of proteins, which are required for central nervous system (CNS) development. COE proteins are highly evolutionarily conserved and regulate neuronal specification, migration, axon guidance, and dendritogenesis during development and are essential for maintaining neuronal identity in adult neurons. Haploinsufficiency of EBF3 may affect brain development and function, resulting in developmental delay, intellectual disability, and behavioral differences observed in individuals with a deleterious variant in EBF3.

A 13-year-old male presented with new onset seizures, sagittal sinus thrombosis with cerebral hemorrhage, and extensive venous thrombosis of the lower limbs. Laboratory investigation demonstrated combined deficiency of protein C, protein S, and antithrombin III. He and his 17-year-old sister had a mental retardation-multiple anomaly syndrome associated with microcephaly, unusual facies, and lax connective tissue. Their dysmorphology included elongated faces with narrow forehead, arched eyebrows, large mouth with down-turned corners, malformed teeth, and furrowed tongue. Both had Marfanoid habitus with lax joints, pectus excavatum, kyphoscoliosis, and flat narrow feet. The most likely diagnosis for these siblings is the autosomal recessive Cohen syndrome of mental retardation, congenital hypotonia with Marfanoid habitus, microcephaly, pleasant affect, micrognathia, and open mouth with prominent incisors. The sagittal sinus thrombosis, left frontal intracranial hemorrhage, carotid aneurysm, tortuous descending aorta, and deep venous thrombosis suffered by the male sibling adds the Cohen syndrome to genetic vasculopathies that may be associated with stroke.

Background The objective of the study was to describe a novel Xp13.2 chromosome microduplication in a child with some features of Turner syndrome but with menorrhagia after normal menarche. We used clinical evaluation and high resolution chromosome (microarray) analysis. Case A 15-year-old girl with typical (short stature, pulmonic stenosis, widely-spaced nipples) and atypical (Madelung deformity, menorrhagia) manifestations of Turner syndrome had a novel chromosome constitution with extra material (microduplication) at band Xq13.2 that contained the X-inactive-specific-transcript locus. She also had connective tissue laxity, suggestive of vessel fragility as a contributor to her menorrhagia as well as her diagnosis of von Willebrand disease. This first case of selective X-inactive-specific-transcript locus duplication suggests a role for gene repression in Turner syndrome and other disorders that affect ovarian function. Conclusion High-resolution chromosome (microarray) analysis, now a standard of care, will provide new insights into adolescents with abnormal growth and reproductive tract symptoms, especially when accompanied by congenital anomalies.

Nine thousand two hundred eighty abnormalities associated with 2,943 abdominal wall defects (AWD) encoded from 1999 to 2008 by the Texas Birth Defects Registry (TBDR) were classified and analyzed for mechanism, beginning with 1,831 gastroschisis cases, 774 (41%) with 2,368 associated anomalies (AA) and 814 of omphalocele, 727 (89%) with 4,092 AA. Typical AA profiles for Trisomy 18 (23% of omphalocele cases) and Beckwith–Wiedemann syndrome (15%) validated registry AA descriptors, chromosome disorders surprisingly accounting for 24% of known conditions with gastroschisis followed by expected amniotic band (ADAM) complex (23%) and amyoplasia/arthrogryposis (16%). Separation of known diagnoses, fetal-stillbirth cases, and transitional or secondary AA left 330 cases of gastroschisis with 594 AA (452 major, 142 minor) and 295 cases of omphalocele with 956 AA (683 major, 273 minor). Anomalies suggestive of vascular origin (intestinal atresias, amyoplasia, bands) were more frequent with gastroschisis and those of defective lateral folding (exstrophies, limb-body wall defects) with omphalocele. Most AA favoring omphalocele had parallel frequencies with gastroschisis, whether by system/region—for example, cardiac AA (10% of cases), contractures (4.7%), limb (3.7%), CNS (3.2%) for gastroschisis versus cardiac (35%), contractures (14%), digestive-excretory-trunk-axial (all ∼11%), CNS (9.9%) for omphalocele—or for particular minor/major AA—for example, micrognathia (0.72% versus 3.3%), spina bifida (0.59% versus 3.9%), anal atresia (0.73% versus 6.4%), two-vessel cord (0.22% versus 5.6%). Similar frequencies of many AA reflective of early patterning support common AWD origin within early developmental fields and reinforce the use of large birth defect numbers from suitably qualified registries to define anomaly mechanism as well as prevalence. © 2015 Wiley Periodicals, Inc.

Wilson disease or hepatolenticular degeneration has a prevalence of 1 in 33,000 and presents with cirrhosis, neuropsychiatric symptoms, and, more rarely, multisystem disease due to abnormal copper accumulation. Initial hepatic disease is seen in 40% including children in the second decade, while neurologic (40%), psychiatric (20%), or mixed presentations are more typical of adults in the third or fourth decade. Hepatic symptoms range from chronic hepatitis to acute liver failure; neuropsychiatric symptoms from personality changes to tremors, dystonia, choreoathetosis, or even psychosis. The triad of low ceruloplasmin, high urine copper, and Kayser–Fleischer ring differentiates Wilson disease from other copper accumulation states, the diagnosis confirmed by DNA test showing mutation of ATP7B membrane ATPase that transports copper into the Golgi apparatus. Therapy with penicillamine, trientine, zinc, or liver transplant for refractory disease is very effective and underlines the importance of early diagnosis in affected patients and their at-risk siblings.

Autosomal dominant (AD) inheritance is determined by the presence of one abnormal gene on one of the autosome (chromosome 1–22).

Here we report on a 39-year-old woman with severe mental retardation, short stature, unusual face with prominent nose, broad thumbs, and broad first toes diagnostic of the Rubinstein-Taybi syndrome. Following admission because of headache and anorexia, a bifrontal lobe neoplasm was excised and diagnosed as an angioblastic meningioma. The unusual tumor and aged appearance of the patient add 2 facets to the natural history of Rubinstein-Taybi syndrome.

Chromosome deletions involving 1p36 are the most common known terminal rearrangements occurring at a frequency of ∼1 in 5,000 live births. In contrast, duplications of the same region have been reported rarely. We describe a familial rearrangement der(1)del(1)(p36.33)dup(1)(p36.33p36.22) identified in a mother, daughter, and son. These individuals help define a syndrome with variable mental disability, attention deficit-hyperactivity disorder, and a distinctive facial appearance with wide palpebral fissures, broad nasal root, macrostomia, ear malformations, and prominent incisors. Based on our results we suggest that the complex rearrangement seen in our family could be the result of the breakage-fusion-bridge (BFB) cycles model of formation. © 2005 Wiley-Liss, Inc.

A 10-month old female is described with inv dup(8)(p12p23) who had macrocephaly with subtle changes in facial appearance and no structural birth defects. Her findings, together with those of 37 reported cases with inv dup (8), define a syndrome that emphasizes the importance of genes on the 8p region for brain development.