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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.

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.)

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.

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.

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.

Exome results are reported for two patients with connective tissue dysplasia, one refining a clinical diagnosis of Ehlers–Danlos to Marfan syndrome, the other suggesting arthrogryposis derived from maternofetal Stickler syndrome. Patient 1 had mutations in transthyretin (TTR), fibrillin (FBN1), and a calcium channel (CACNA1A) gene suggesting diagnoses of transthyretin amyloidosis, Marfan syndrome, and familial hemiplegic migraines, respectively. Patient 2 presented with arthrogryposis that was correlated with his mother's habitus and arthritis once COL2A1 mutations suggestive of Stickler syndrome were defined. Although DNA results often defy prediction by the best of clinicians, these patients illustrate needs for ongoing clinical scholarship (e.g., to delineate guidelines for management of mutations like that for hyperekplexia in Patient 2) and for interpretation of polygenic change that is optimized by clinical genetic/syndromology experience (e.g., suggesting acetazolamide therapy for Patient 1 and explaining arthrogryposis in Patient 2). © 2014 Wiley Periodicals, Inc.

Mammalian genes encoding a 35-kDa peroxisomal membrane protein (PMP35, peroxisome assembly factor-1) are compared using the polymerase chain reaction and DNA sequencing. DNA sequencing of the 915 bp of the PMP35 coding regions was in complete agreement with previously published rat data and showed 36 and 133 nucleotide substitutions, respectively, in mouse and man. The 12 and 35 respective amino acid changes encoded by these nucleotide substitutions are clustered and compatible with putative membrane-spanning regions. Rat/human and rat/mouse comparisons yield silent mutation rates of 0.33 and 0.21% per site per million years and replacement mutation rates of 0.082 and 0.076%; transitions account for 67% (human/mouse) and 83% (rat/mouse) of nucleotide replacements among PMP35 genes. PMP35 gene expression in mouse tissues as measured by reverse transcriptase-PCR was responsive to clofibrate and disproportionately high in neural tissue.

We describe a boy with short stature, developmental delay, unusual face, right iris coloboma, malformed ears, micrognathia, and skeletal anomalies including hyperphalangy of the index fingers, bilateral fifth finger clinodactyly, short halluces, and scoliosis. Internal anomalies included asymmetric and dilated cerebral ventricles and ventricular septal defect. The neonatal history of small jaw with feeding and respiratory difficulties suggested a Pierre Robin sequence, but there was no cleft palate. Two maternal uncles with similar anomalies had died at ages 13 months and 5 years, respectively. RFLP studies with the DNA probes DXS72 and F8C were consistent with but not diagnostic of X-linked recessive inheritance. The pattern of anomalies was compatible with a diagnosis of Catel-Manzke syndrome, but a novel dysostosis syndrome must also be considered.

An 18-year-old female with mild mental disability (global IQ 69), febrile seizures with subsequent myoclonic/grand mal epilepsy, and subtle morphologic changes is described with del 5(q14.3q21.3) by karyotype and minimal DNA deletion of 21.08 Mb by array comparative genomic hybridization microarray analysis (arr chr5:83,592,798-104,671,993 X1) that encompasses at least 50 genes. Included in the deletion interval is the MEF2C gene that usually causes severe mental disability when haploinsufficient, illustrating the complexity of clinic-cytogenetic correlation even with defined segmental aneuploidy. Interaction of MEF2C with the deleted febrile seizure (FEB4) and juveline myoclonic epilepsy (EJM4) loci plus the G-protein receptor (GPR98/MASS1/Usher syndrome) gene may moderate the phenotype, perhaps through common regulation by calcium.

A survey of Mendelian Inheritance in Man emphasizes the large Mendelian contribution to human dysmorphogenesis and contrasts single gene conditions with chromosomal disorders. There were 1761 conditions that involved altered morphogenesis (49% of disease entries), including 1040 multiple defect syndromes and 721 inherited single birth defects. Premature death (36-57%), mental retardation (20-59%), and growth retardation (37-59%) are more frequent in autosomal recessive or X-linked syndromes, while predisposition to tumorigenesis was more common in dominant (16%) than recessive (3.4%) syndromes. Comparison of the Mendelian conditions with 100 chromosomal disorders showed a strikingly similar spectrum of malformation, with skeletal, craniofacial, eye, epidermal, and neuromuscular systems being most frequently affected. Chromosomal syndromes average 10.6 systems affected per disorder, in contrast to 3.55 for Mendelian syndromes, and pleiotropy does correlate weakly with aneuploid segment length. Genomic understanding of these relationships is still primitive, with 74 of 1609 (4.6%) autosomal conditions and 43 of 152 (29%) X-linked conditions mapped to specific chromosomal regions. The societal toll of human dysmorphogenesis and the evident progress with X-linked disorders provide a powerful rationale for the Human Genome Project.

Peroxisomal membrane proteins (PMPs) from the Swiss-Webster mouse are analyzed and compared to those of rats and humans using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. A purification procedure for fresh mouse, rat, or human biopsy liver which enriches peroxisomal/mitochondrial marker enzyme ratios over 100-fold is characterized. When analyzed by SDS-PAGE, membranes of purified liver peroxisomes are shown to contain the same complement of 145-, 70-, 55-, 36-, and 22-kDa PMPs in rats, mice, and humans. A rabbit polyclonal antibody raised against mouse peroxisomal membranes demonstrates immunoreactivity to 145- and 70-kDa proteins in fresh liver homogenates from all three species and in control or Zellweger syndrome fibroblasts from humans. Human autopsy or placental tissues which were refrigerated before analysis exhibited 105-, 55-, and 36-kDa peptides which may be derived from the 145- and 70-kDa peptides. Such conversions, if related to degradation, may explain difficulties in purifying peroxisomes from human autopsy specimens. Variable amounts of the 55-kDa peptide also occurred in mouse adrenal and lung, and the conversion of higher to lower molecular weight PMPs could not be demonstrated by in vitro incubation of mouse liver. Further definition of the structure and variability of mammalian PMPs should be helpful in understanding polyenzymopathies such as Zellweger syndrome.

A 14-year-old girl with ichthyosis and severe liver disease is compared to 35 reported cases of KID or Senter syndrome. Common manifestations such as ichthyosis (35/35 patients), sensorineural deafness (33/34), "ectodermal dysplasia" (25/28), corneal abnormality (26/31) were present in the proposita, while less common manifestations such as chronic infections (15/20) and neuromuscular disease (12/35) were absent. Two families with vertical transmission and 28 sporadic cases are compatible with an autosomal dominant form of KID syndrome, while one inbred sibship with liver disease suggests the existence of an autosomal recessive form. The proposita was similar to the latter patients in having progressive cirrhosis necessitating liver transplantation; she also had short stature (10/35 patients) and mental retardation (3/35). Hepatic findings included micronodular cirrhosis, cholestasis, hyperplastic Kupffer cells, abundant Mallory's hyaline, copper accumulation without steatosis, and normal peroxisomes.

Studies in "lower" organisms have identified a set of homologous sequences expressed in oocytes and early embryos that is critical for pattern formation. Mutations in such genes may exhibit maternal effect--they cause abnormalities in the fetus only when present in the mother. We report on a mother and child with identical, apparently balanced translocations having the breakpoints 12q13.1 and 13p13. The fetus had multiple anomalies including bilateral trilobar lungs, complex heart defect, malrotation of the gut, and asplenia, while the mother was entirely normal. Several hypotheses are advanced to explain this variable expression including transection of a gene with maternal effect--lateral asymmetry in the fetus is influenced by the maternal genotype. This explanation would account for the higher transmission of congenital heart disease to offspring by affected females noted in several studies. The human counterparts of 2 loci (int-1 and HOX 3) involved in Drosophila early pattern formation are located near the translocation breakpoint 12q13.1. If one of these genes is responsible for situs abnormality, then university of positional code (but not of embryologic mechanism) is suggested for higher metazoans.

The frequency of abortion following chorionic villus sampling (CVS) is similar to that following amniocentesis. However, there is no information on long-term effects, such as malformations in liveborn children exposed to CVS. We evaluated 189 infants whose mothers had either CVS or amniocentesis as participants in the Canadian Collaborative Randomized Trial, a prospective assessment of the safety of CVS compared with amniocentesis. The participation rate of children who could be contacted was 95%. Ninety-five of the 189 infants (50.2%) had been exposed to CVS, 87 (46%) to amniocentesis, and 7 (3.8%) to both. (The latter group was excluded from calculations.) One hundred twenty-eight (128) children had greater than or equal to one minor anomalies but no major abnormalities: 58 of 95 (60%) in the CVS and 70 of 87 (80%) in the amniocentesis group. Twenty-six children had malformations: 17 (17.8%) in the CVS and 9 (10.3%) in the amniocentesis group. Only one anomaly, Sturge-Weber dysplasia (amniocentesis group), was potentially severe and none were life-threatening. Superficial cavernous hemangiomas (strawberry nevi) were noted more frequently in children in the CVS group (12.6%) than in the amniocentesis group (3.4%), but only slightly higher than in the general public. We conclude that exposure to CVS is not associated with an increased frequency of malformations or minor anomalies in infants compared with amniocentesis although we observed a higher frequency of superficial cavernous (strawberry) hemangiomas in the children in the CVS group.

Alternative explanations for aneuploid phenotypes are evaluated according to clinical and experimental predictions. The additive hypothesis views the diverse manifestations of aneuploidy as the simple sum of individual gene dosage effects. The interactive hypothesis views aneuploid characteristics as network properties of genes within and outside the aneuploid segment. The importance and historical context of this debate are emphasized, and the 2 hypotheses are contrasted in terms of their experimental predictions and explanatory power. In particular, the concepts of colinearity and continuity derived from single gene action are explicitly examined in human aneuploidy with the conclusion they are likely to be false assumptions.

Knowledge of a few disease categories and their associated laboratory tests can award the pediatrician full partnership in the management of genetic disease. The provision of a DNA test for cystic fibrosis is a recent example of the important advances occurring in genetics. Only the enlightened practitioner can ensure that patients have full and proper access to such advances.

A newborn female presented with costovertebral dysplasia (CVD), subtle facial anomalies, and neonatal respiratory distress. Her karyotype demonstrated a small supernumerary NOR-positive marker that was subsequently identified as del(22)(q11.2). This extra structurally abnormal chromosome was found by DNA microsatellite marker analyses to be derived from a paternal chromosome 22. The child has had severe growth and developmental delay along with pulmonary insufficiency and hypoxia but is presently stable at age 20 months. Findings in our patient correlate with similar observations in children with small markers derived from D/G and D/D translocations reported before banding technology was available. These reports and recent mapping results suggest that a pericentric gene family, distributed on one or more acrocentric chromosomes, may have played a role in the development of the human axial skeleton. Data from additional studies will be needed to confirm or refute this hypothesis.

The behavior of 60 children with Down syndrome (cDS), aged 4 to 21 years, was assessed by parent and teacher report using the Reiss psychopathology rating scale for dual diagnosis (mental disability plus mental illness). Standard forms contained 12 categories of abnormal behavior (e.g., Psychosis), each with five descriptive items (e.g., bizarre ideas) that could be scored as no problem, problem, and major problem (0, 1, or 2 points). Total scores for individual cDS (mean of two raters) ranged from 3 to 43 out of a potential 120 points, with a mean of 14.8 points and a standard deviation of 9.5. There were no significant differences by sex, age, or ethnicity. The highest aggregate scores among the 60 cDS were in the psychometric categories of Attention-Deficit (156 points), Anger/Self Control (154.5), and Psychosis (109) and for component items such as communication problems (55 points) under the Psychosis category; distracted (48.5) or disobedient (42.5) under the Attention-Deficit category; and temper tantrums (36.5), impulsive (32), or impatient (31.5) under the Anger/Self-Control category. Agreement between parent and teacher raters was over 75% for 38 of the 60 items and above 60% for an additional 15. Selection of cDS with scores over 10 points yielded 24 families who chose parental guidance and 14 who chose professional referral. The structure of the Reiss instrument was useful for cDS, distinguishing behaviors potentially related to medical problems from true psychopathology.

We describe a female infant with morphologic features of Rutledge multiple-congenital-anomaly syndrome (RM-CAS) and biochemical features of Smith-Lemli-Opitz syndrome (SLOS). She had microcephaly with hypoplastic cerebral frontal lobes and cerebellum, agenesis of the splenium of corpus callosum, abnormal facies including hypertelorism with bilateral inner epicanthal folds, a broad nasal bridge with slightly anteverted nares and patent choanae, low set ears and complex conchal formation, high-arched palate and thick maxillary alveolar ridges, and micrognathia. Her chest was broad, genitalia were ambiguous, and uterus was bicornuate. Skeletal abnormalities included a hypoplastic appendicular skeleton, post-axial hexadactyly of the right hand and the left foot, syndactyly of bilateral 2nd–3rd toes and left 5th–6th toes, right talipes varus and left talipes valgus, and fused L5–S1 vertebrae. Congenital heart disease consisted of hypoplastic left heart, coronary sinus agenesis, ostium secundum and ostium primum defects, and a thickened septum primum. The lungs were hypolobated and the kidneys manifested oligopapillary hypoplasia. Total colonic Hirschsprung disease was noted microscopically. Analysis of liver tissue taken at postmortem examination revealed the ratio of 7-dehydrocholesterol and cholesterol to be 143 (expected, 0.28 ± 0.28). Although initially described as a distinct syndrome, RMCAS was merged with the severe form of SLOS, because of significantly overlapping features [Online Mendelian Inheritance in Man (OMIM) #268670]. The biochemical data showing an excess of 7-dehydrocholesterol and low cholesterol in the liver tissue of our case supports this viewpoint.

Two families and 3 patients with dup(10p)/del(10q) syndrome segregating from a maternal pericentric inversion are described, including a stillborn female with Potter sequence and multicystic renal dysplasia. Comparison of 32 dup(10p) patients to 11 del(10)(q25) patients emphasized dolichocephaly, wide sutures, frontal bossing, micrognathia, and renal defects as distinguishing characteristics of the dup(10p) syndrome. The 3 new and 6 previously reported dup(10p)/del(10q) patients had several manifestations in common with the dup(10p) and del(10q) syndromes, but were more typical of dup(10p) syndromes, with respect to all 5 distinguishing characters. © 1993 Wiley-Liss, Inc.

A heteromorphism of the short arm of 16 (16p+) was discovered in 2 unrelated infants. By G banding, the euchromatic variant appears as a light and a medium dark band just distal to the centromere. This results in an increase of the short arm by about 1/3. The same variant was present in the normal father and the normal paternal grandmother in one family and mildly retarded mother in the 2nd family. The anomalies of the 2 infants are not similar and are apparently unrelated to the 16p + variant. Though the discovery of such euchromatic variants is highly significant for clinical diagnosis, their genetic significance and mode of origin remain to be elucidated.

FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at θ = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, θ = 0, α = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region. Am. J. Med. Genet. 73:87–90, 1997. © 1997 Wiley-Liss, Inc.

We describe clinical and chromosomal findings in two patients with del(4q). Patient 1, with interstitial deletion (4)(q21.1q25), had craniofacial and skeletal anomalies and died at 8 months of hydrocephalus. Patient 2, with interstitial deletion (4)(q25q27), had craniofacial and skeletal anomalies with congenital hypotonia and developmental delay. These patients shared certain manifestations with other del(4q) patients but did not have Rieger anomaly. Clinical variability among patients with interstitial deletions of 4q may be related to variable expression, variable deletion, or imprinting of genes within the 4q region.

MASA syndrome is a recessive X-linked disorder characterized by mental retardation, adducted thumbs, shuffling gait, aphasia and, in some cases, hydrocephalus. Since it has been shown that X-linked hydrocephalus can be caused by mutations in L1CAM, a neuronal cell adhesion molecule, we performed an L1CAM mutation analysis in eight unrelated patients with MASA syndrome. Three different L1CAM mutations were identified: a deletion removing part of the open reading frame and two point mutations resulting in amino acid substitutions. L1CAM, therefore, harbours mutations leading to either MASA syndrome or HSAS, and might be frequently implicated in X-linked mental retardation with or without hydrocephalus.

We describe a 5-generation Hispanic family with 13 males and 1 female affected with MASA syndrome. The proposita, a 17-year-old female, and her affected male relatives shared many of the cognate manifestations--mental retardation (14/14), aphasia or delayed speech (13/13), shuffling gait (8/13), adduction of thumbs (14/14)--as well as scoliosis (2/13) and increased deep tendon reflexes in the lower extremities (10/13). Southern analysis with the polymorphic DNA probes DXS14 (Xp11), DXS72 (Xq21), and F8C (Xq28) confirmed linkage to the Xq28 region with a maximum lod score of 3.01 for this family.

Progress relevant to human peroxisomal disorders over the past 3 years includes improved biochemical delineation of disease phenotypes and new insights into peroxisomal structure and biogenesis. Immunoblotting studies using antibodies to peroxisomal β-oxidation enzymes have defined mutations affecting each step of the pathway, some with clinical phenotypes as severe as disorders with global peroxisome deficiency. The latter disorders, typified by Zellweger syndrome, often lack matrix proteins but retain major membrane species of 150, 70, 35, and 22 kDa in empty peroxisomal “ghost” structures. The hypothesis that peroxisomal deficiency disorders result from altered targeting or import of peroxisomal matrix proteins has been strengthened by the demonstration of a carboxy terminal peroxisome-targeting signal which is distinct from amino terminal signals directing proteins to mitochondria. A mutation which mistargets alanine/glyoxylate aminotransferase from peroxisomes to mitochondria in primary hyperoxaluria provides a graphic example of these signals. The structural significance of membrane function is supported by the primacy of membrane assembly in normal ontogeny or regenerating liver. The coordinate control, targeting, and striking inducibility of peroxisomal proteins suggests a potential vehicle for gene and enzyme therapy.

An 11-year-old patient with incomplete testicular feminization and a 47,XXY karyotype is described. The patient had female external genitalia, clitoromegaly, and some features of Klinefelter's syndrome, including speech delay and delayed intellectual development. DNA analysis using X chromosomal DNA sequences suggests that the supernumerary X chromosome in the patient resulted from maternal nondisjunction during meiosis II. The M II error thereby provides the basis for homozygosity of a mutation in the androgen receptor locus.

Named for their common impact on bone histogenesis, the category of skeletal dysplasias contains over 100 entities of sporadic, teratogenic, or genetic etiology.

Four patients are presented with the Goldenhar syndrome (GS) and cranial defects consisting of plagiocephaly, microcephaly, skull defects, or intracranial dermoid cysts. Twelve cases from the literature add hydrocephalus, encephalocele, and arhinencephaly to a growing list of brain anomalies in GS. As a group, these patients emphasize the variability of GS and the increased risk for developmental retardation with multiple, severe, or unusual manifestations. The temporal relation of proposed teratogenic events in GS provides an opportunity to reconstruct biological relationships within the 3-5-week human embryo.

The Zellweger cerebro-hepato-renal syndrome is a genetic disease characterized by the absence of peroxisomes and deficiency of glycerol-ether lipids in several tissues. We measured the activity of dihydroxyacetone phosphate (DHAP) acyltransferase, a peroxisomal enzyme with a major role in ether lipid synthesis, in fibroblasts and leukocytes from patients with Zellweger syndrome. Control skin and amniotic-fluid fibroblasts had normal activity of DHAP acyltransferase (0.28 to 0.3 nmol per minute per milligram of protein), whereas fibroblasts from three patients with Zellweger syndrome had deficient activity (0.013 +/- 0.006 nmol per minute per milligram of protein). The activity of the enzyme in leukocytes and levels of plasmalogens (the major class of cellular glycerol-ether lipids) in erythrocytes were also deficient in a patient, but normal levels of leukocyte enzyme and erythrocyte plasmalogens were found in her parents. Other enzymes of the acyl DHAP pathway exhibited alterations in fibroblasts from patients with Zellweger syndrome, and the activity of the glycerophosphate acyltransferase was also reduced. These results support prior studies emphasizing the role of peroxisomes and the acyl DHAP pathway in cellular ether lipid synthesis, establish Zellweger syndrome cells as valuable for elucidating peroxisomal functions, and provide prenatal and postnatal diagnostic assays as well as potential therapeutic strategies for Zellweger syndrome.

Eco-RI-A fragments of the human ribosomal RNA gene family from two types of tissue and three individuals were cloned in λ vectors and compared by restriction enzyme digestion and electron microscopy. The EcoRI fragment A contains (i) 0.2 kb of the 3' end of the 18S rDNA, (ii) 2.5 kb of internal transcribed spacer and the 5.8S rDNA, and (iii) 4.6 kb of the 28S rDNA gene. All of the six cloned rDNA fragments isolated are identical by these analyses. Moreover, all contain a HincII site that is absent in about 50% of the rDNA identified by genomic blotting. Polymorphism in the nontranscribed spacer rDNA was studied on genomic blots of BamHI-digested DNA, using the 3' end of the 28S rDNA as a probe. The boundaries between the 18S rDNA, internal transcribed spacer, 28S rDNA, and external nontranscribed spacer were determined by R-loop analysis, further defining the organization of the ribosomal RNA precursor.

We report seven infants of diabetic mothers, affected with holoprosencephaly malformation sequence. An additional 15 cases assembled from personal communications and the literature indicate that holoprosencephaly, like neural tube, cardiac, and caudal defects, is specifically increased in children of diabetic mothers. Incidence figures from newborn surveys demonstrate a risk for holoprosencephaly in infants of diabetic mothers comparable to the 1% risk for caudal regression malformation sequence. The embryologic timing of cranial, cardiac, and caudal defects emphasizes the need for pregnancy planning and diabetes control.

We report on a 3-month-old girl with unusual facial appearance, short neck with low posterior hairline, wide chest, valvular pulmonic stenosis, abnormal fingernails, and diploid-tetraploid mosaicism (46,XX/92,XXXX in 7.2% of peripheral leucocytes and in 29% of skin fibroblasts). Comparison with 11 previously reported cases with mosaic or complete tetraploidy does not establish an easily recognizable syndrome. However, a malformation pattern is apparent when tetraploidy patients are compared with 14 cases of triploid mosaicism and 44 previously reported cases of nonmosaic triploidy. A history of sex hormone exposure was present in 5 of 11 pregnancies resulting in tetraploidy; this exposure may correlate with the occurrence of tetraploidy in polycystic ovary syndrome and in tumors of the female reproductive tract. The mechanism of dysmorphogenesis involved in polyploidy is considered, including hypotheses of altered nuclear/cytoplasmic ratio, of trophoblastic alteration, of delayed cell division, or of altered autosome/active X chromosome ratio.

From January, 1981 through June, 1982 specimens from 21 patients with bladder (urothelial) cancer were placed in tissue culture, and one long term cell line was established (5%). From July, 1982 through February, 1984, using an improved culture medium, seven long term cell cultures were established from 21 patients (33%). In addition, one long term culture from a patient with a bladder melanoma was established using the standard culture medium. The nine cell cultures were derived from the following types of tumors: transitional cell carcinoma (6), adenocarcinoma (1), squamous cell carcinoma (1) and melanoma (1). All of the cell lines have produced tumors in athymic nude mice except for one transitional cell carcinoma. All of the cultures demonstrate aneuploidy. Homogeneously staining regions have been seen in some cell cultures. A common marker chromosome has not been identified.