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GRID1 and GRID2 encode the enigmatic GluD1 and GluD2 proteins, which form tetrameric receptors that play important roles in synapse organization and development of the central nervous system. Variation in these genes has been implicated in neurodevelopmental phenotypes. We evaluated GRID1 and GRID2 human variants from the literature, ClinVar, and clinical laboratories and found that many of these variants reside in intolerant domains, including the amino terminal domain of both GRID1 and GRID2. Other conserved regions, such as the M3 transmembrane domain, show different intolerance between GRID1 and GRID2. We introduced these variants into GluD1 and GluD2 cDNA and performed electrophysiological and biochemical assays to investigate the mechanisms of dysfunction of GRID1/2 variants. One variant in the GRID1 distal amino terminal domain resides at a position predicted to interact with Cbln2/Cbln4, and the variant disrupts complex formation between GluD1 and Cbln2, which could perturb its role in synapse organization. We also discovered that, like the lurcher mutation (GluD2-A654T), other rare variants in the GRID2 M3 domain create constitutively active receptors that share similar pathogenic phenotypes. We also found that the SCHEMA schizophrenia M3 variant GluD1-A650T produced constitutively active receptors. We tested a variety of compounds for their ability to inhibit constitutive currents of GluD receptor variants and found that pentamidine potently inhibited GluD2-T649A constitutive channels (IC50 50 nM). These results identify regions of intolerance to variation in the GRID genes, illustrate the functional consequences of GRID1 and GRID2 variants, and suggest how these receptors function normally and in disease., (© The Author(s) 2023. Published by Oxford University Press.)

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS., (© 2023. The Author(s).)

Purpose: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized., Methods: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system., Results: Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder., Conclusion: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)

Purpose: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu)., Methods: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics., Results: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production., Conclusion: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis., (Copyright © 2019 American Society of Human Genetics. All rights reserved.)

The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other "spliceosomopathies" linked to variants that drive multi-system congenital defects and are found in hnRNPs., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

A 14-month-old child, recently diagnosed with Niemann-Pick disease type A, presented for a laparoscopic placement of a gastrostomy tube under general anesthesia. The disease was confirmed and further characterized by genetic testing, which revealed evidence of the presence of two known pathogenic mutations in the SMPD1 gene, and enzyme studies showed a corresponding very low level of enzymatic activity of acidic sphingomyelinase. The anesthetic management involved strategies to manage an anticipated difficult intubation and avoid post-operative ventilation.

Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a ∼465 kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes., (Copyright © 2012 Wiley Periodicals, Inc.)

Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.

Purpose: Enzyme replacement therapy with rhGAA (Myozyme®) has lead to improved survival, which is largely attributable to improvements in cardiomyopathy and skeletal muscle function. However, crossreactive immunologic material-negative patients have a poor clinical response to enzyme replacement therapy secondary to high sustained antibody titers. Furthermore, although the majority of crossreactive immunologic material-positive patients tolerize or experience a downtrend in anti-rhGAA antibody titers, antibody response is variable with some crossreactive immunologic material-positive infants also mounting high sustained antibody titers., Methods: We retrospectively analyzed 34 infants with Pompe disease: 11 crossreactive immunologic material-negative patients, nine high-titer crossreactive immunologic material-positive patients, and 14 low-titer crossreactive immunologic material-positive patients. Clinical outcome measures were overall survival, ventilator-free survival, left ventricular mass index, Alberta Infant Motor Scale score, and urine Glc(4) levels., Results: Clinical outcomes in the high-titer crossreactive immunologic material-positive group were poor across all areas evaluated relative to the low-titer crossreactive immunologic material-positive group. For the crossreactive immunologic material-negative and high-titer crossreactive immunologic material-positive groups, no statistically significant differences were observed for any outcome measures, and both patient groups did poorly., Conclusions: Our data indicate that, irrespective of crossreactive immunologic material status, patients with infantile Pompe disease with high sustained antibody titer have an attenuated therapeutic response to enzyme replacement therapy. With the advent of immunomodulation therapies, identification of patients at risk for developing high sustained antibody titer is critical.

Humans with mosaic karyotypes may present with milder forms of birth defects than one would see in non-mosaic individuals. Mosaicism may also affect tissues, resulting in different parts of an organ manifesting varied phenotypes. We present the case of a child born with mosaic trisomy 9 and multiple congenital anomalies. Her trachea displays segmental abnormalities that suggest tissue mosaicism. We describe the endoscopic and cytogenetic findings in this child and propose a possible genetic mechanism to account for the unusual malformations., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is a rare autosomal-recessive neurological disorder showing highly characteristic clinical and neuroradiological features. Affected individuals demonstrate early-onset seizures, severe microcephaly, and developmental arrest with bilateral, symmetrical polymicrogyria (PMG) and a band of gray matter calcification on brain imaging; as such, the disorder can be considered as a "pseudo-TORCH" syndrome. By using autozygosity mapping and copy number analysis we identified intragenic deletions and mutations in OCLN in nine patients from six families with BLC-PMG. The OCLN gene encodes occludin, an integral component of tight junctions. Neuropathological analysis of an affected individual showed similarity to the mouse model of occludin deficiency with calcification predominantly associated with blood vessels. Both intracranial calcification and PMG are heterogeneous in etiology. Neuropathological and clinical studies of PMG have suggested that in utero ischemic or vascular insults may contribute to this common cortical abnormality. Tight junctions are functional in cerebral blood vessels early in fetal development and continue to play a vital role in maintenance of the blood-brain barrier during postnatal life. We provide evidence that the tight junction protein occludin (encoded by the OCLN gene) is involved in the pathogenesis of malformations of cortical development., (2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Patients with trisomies or duplications of distal 15q have rarely been reported in the literature. Previous authors [Zollino et al., 1999: Am J Med Genet 87:391-394] have described a distal 15q trisomy syndrome, including the unusual features of prenatal overgrowth, tall stature, macrocephaly, and craniosynostosis. We report three new patients with a duplication of 15q24-q26.3; features common to the two surviving patients include ptosis, small size, and developmental delay. None of these patients had craniosynostosis or overgrowth. We propose that the previously described distal 15q trisomy syndrome [Zollino et al., 1999: Am J Med Genet 87:391-394] may result from specific disruption of a gene linked to 15q25, rather than partial trisomy for the region., (Copyright 2003 Wiley-Liss, Inc.)

Attention deficit disorder (ADHD) is a complex biobehavioral phenotype which affects up to 8% of the general population and often impairs social, academic, and job performance. Its origins are heterogeneous, but a significant genetic component is suggested by family and twin studies. The murine strain, coloboma, displays a spontaneously hyperactive phenotype that is responsive to dextroamphetamine and has been proposed as a genetic model for ADHD. Coloboma is a semi-dominant mutation that is caused by a hemizygous deletion of the SNAP-25 and other genes on mouse chromosome 2q. To test the possibility that the human homolog of the mouse coloboma gene(s) could be responsible for ADHD, we have carried out linkage studies with polymorphic markers in the region syntenic to coloboma (20p11-p12). Five families in which the pattern of inheritance of ADHD appears to be autosomal dominant were studied. Segregation analysis of the traits studied suggested that the best fitting model was a sex-influenced, single gene, Mendelian pattern. Several genetic models were evaluated based on estimates of penetrance, phenocopy rate, and allele frequency derived from our patient population and those of other investigators. No significant linkage was detected between the disease locus and markers spanning this chromosome 20 interval.

Acute leukemia in Down syndrome (DS) is often associated with additional changes in the number or structure of chromosome 21. We present two DS patients whose leukemic karyotypes were associated with changes in chromosome 21 ploidy. Patient 1 developed acute lymphocytic leukemia (type L1); disomy for chromosome 21 was evident in all blast cells examined. Loss of the paternal chromosome in the leukemic clone produced maternal uniparental disomy with isodisomy over a 25-cM interval. The second patient had acute monoblastic leukemia (type M5) with tetrasomy 21 in all leukemic cells. DNA polymorphism analysis showed duplicate paternal chromosomes in the constitutional genotype. The maternal chromosome was subsequently duplicated in the leukemic clone. The distinct inheritance patterns of chromosome 21 in the blast cells of these patients would appear to indicate that leukemogenesis occurred by different genetic mechanisms in each individual.

We describe 2 children with severe ptosis, trigonocephaly, broad nasal bridge, and major brain malformation. A total of 8 children have been reported who share most of these findings. Two of the individuals have had identical pericentric inversions involving chromosome 2p12-q14. These cases appear to represent a unique malformation syndrome.

A family with five members who have variable findings of leuconychia, knuckle pads, hearing loss, and palmoplantar hyperkeratosis is described. The findings in these subjects are compared with those noted in previously reported patients with Bart-Pumphrey syndrome. The range of disorders which include knuckle pads as part of the phenotype is reviewed.

Brothers were affected with severe congenital contractures, multiple cutaneous manifestations of ectodermal dysplasia, cleft lip/palate, and psychomotor and growth impairment. High resolution prometaphase chromosomes were normal. Molecular studies of DNA markers, closely flanking the X-linked hypohidrotic ectodermal dysplasia locus, did not show evidence of a submicroscopic deletion from the Xq12-q13 region. The parents and a normal sister exhibited none of these findings. This constellation of anomalies appears to represent a unique AR or XLR syndrome.

Hemizygous deletion of 3p25-pter is associated with a phenotype of profound growth failure, microcephaly, characteristic facial changes, and mental retardation. Since the severity may be quite variable, we have studied 3 cases of del 3p25-pter to define the clinical manifestations and the critical chromosome region for phenotypic expression. The patient we now report died at age 6 months and provided an opportunity for a detailed necropsy analysis for only the second time in a del(3p) patient. He had marked hypoplasia of all organs, hypomyelination of white matter, and multiple renal cortical microcysts. Ordered genomic markers from the distal regions of chromosome 3p aided in determining the parent of origin of each deletion and in defining the boundaries of the deleted chromosomal segments. The deleted markers distal to the RAF1 oncogene in 2 of the 3 patients were consistently hemizygous. One patient had an interstitial deletion based on evidence of diploid inheritance of one of the most distal loci (D3S17). Available genetic linkage maps suggest that the deletion spans at least 19 centimorgans (cM).

Neurologic abnormalities have been described only once previously in a child with Weissenbacher-Zweymüller syndrome (WZS), a rare skeletal dysplasia, evident neonatally. We report on identical twin male infants with skeletal findings typical of WZS, including small size at birth, proximal limb shortness, mid face hypoplasia, and myopia. In addition, twin B had a parieto occipital encephalocele while twin A had a meningocele at the same location. Twin B has had significant delays in development and hearing loss.

The physical, radiographic, and pathologic findings in 3 new patients with Marden-Walker syndrome (MWS) are compared with those of previously described children with the syndrome. Over 75% of the children with MWS have blepharophimosis, psychomotor retardation, small mouth, micrognathia, kyphosis/scoliosis, and multiple contractures. Minimal diagnostic criteria have yet to be defined attesting to the broad range of variability and potential genetic heterogeneity in this disorder.

Mutations in the genes coding for the pro alpha 1 and pro alpha 2 chains of type I procollagen have been found in many patients with osteogenesis imperfecta (OI), a heritable disorder of connective tissue. The severity of the disease varies between families and even among members of the same family. This phenotypic variability covers a spectrum extending from very mild forms that cannot be easily detected to perinatally lethal forms. One explanation for this phenotypic variability is the nature of the mutation in the type I procollagen genes. Another explanation is mosaicism. Here we report on 2 families with propositi who have OI, whereas their mothers had a milder form of the disease. In one family, the molecular defect was previously shown to be a substitution of alpha 1(904) by cysteine [Constantinou et al., 1990]. The biochemical phenotype was characterized by significant post-translational overmodification of the mutated type 1 collagen molecules which also had a 3-4 degrees C decrease in their thermal unfolding. Also, secretion of the procollagen into the culture media was delayed. In the second family, the proposita's muscle fibroblasts synthesized and secreted type I procollagen molecules that were highly over-modified along the entire length of their triple-helical domain. Cells from the mother also synthesized normal and over-modified protein, although the amount of over-modified protein was less than that synthesized by her daughter's cells. The exact molecular defect has not yet been defined.(ABSTRACT TRUNCATED AT 250 WORDS)

A large frontal bone defect underlying a "V" shaped scar was noted in a newborn male whose mother had an identical "V" shaped scar at the same location in the anterior hairline. Both had hypertelorism and short palpebral fissures. The mother had no radiographic evidence of skull defect and neither mother nor child had other cutaneous or skeletal anomalies. Cranioplasty was performed on the child using the remaining frontal bones with an excellent cosmetic result. Biopsy performed at operation documented scar tissue extending through the dermis and underlain by thickened dura. Mother and child appear to have a variant form of aplasia cutis congenita, an autosomal dominant trait with wide variation in expression.

Background: Prader-Willi syndrome is a genetic disorder characterized by infantile hypotonia, obesity, hypogonadism, and mental retardation, but it is difficult to diagnose clinically in infants and young children. In about two thirds of patients, a cytogenetically visible deletion can be detected in the paternally derived chromosome 15 (15q11q13). Recently, patients with Prader-Willi syndrome have been described who do not have the cytogenetic deletion but instead have two copies of the 15q11q13 region that are inherited from the mother (with none inherited from the father). This unusual form of inheritance is known as maternal uniparental disomy. Using molecular genetic techniques, we sought to determine the frequency of uniparental disomy in Prader-Willi syndrome., Methods: We performed molecular analyses using DNA markers within 15q11q13 and elsewhere on chromosome 15 in 30 patients with Prader-Willi syndrome who had no cytogenetically visible deletion. We also studied their parents. Three patients with Prader-Willi syndrome who had a cytogenetic deletion served as controls., Results: In 18 of the 30 patients without a cytogenetic deletion (60 percent), we demonstrated the presence of maternal uniparental disomy for chromosome 15 and its association with advanced maternal age. In another eight patients (27 percent), we identified large molecular deletions. The remaining four patients (13 percent) had evidence of normal biparental inheritance for chromosome 15; three of these patients were the only ones in the study who had some atypical clinical features., Conclusions: In about 20 percent of all cases, Prader-Willi syndrome results from the inheritance of both copies of chromosome 15 from the mother (maternal uniparental disomy). With the combined use of cytogenetic and molecular techniques, the genetic basis of Prader-Willi syndrome can be identified in up to 95 percent of patients.

We describe a child with multiple anomalies and severe retardation with dup 7pter-p15.1 and del 7q36-qter as a result of a parental pericentric inversion of chromosome 7. The pericentric inversion was found in family members in 3 generations with 9 liveborn children who had severe anomalies probably associated with imbalances of chromosome 7.

A 20-week fetus affected with cerebro-ocular dysplasia and muscular dystrophy (Walker-Warburg Syndrome) is reported. The central nervous system (CNS) findings were typical of those previously described in this disorder, and were characterized by lissencephaly, hydrocephalus, and cerebral and cerebellar cortical dysplasia with glial and neuronal displacement into the leptomeninges. In addition, severe hypoplasia of pyramidal tracts were noted in the brain stem and spinal cord, as well as malformation of the inferior olivary and dentate nuclei. Skeletal muscle and eyes appeared normal on light microscopy. The genetic defect in this disorder is expressed in the CNS early during the first trimester and causes a marked disorder of cellular migration. Overt changes in muscle occur during a later period. The changes in the CNS are similar to, but more severe than, those found in Fukuyama congenital muscular dystrophy, and both may represent a failure of constraint of neuronal migration. Whether the syndromes characterized by cerebro-ocular dysplasia and muscular dystrophy are genetically heterogeneous or allelic variations is unknown. Molecular genetic analysis should elucidate this question.

Five matings to a dir ins (6;2)(q16;q31q33) carrier have produced a high frequency (42%) of offspring with unbalanced karyotypes. Five children have the derivative chromosome 2 resulting in del (2)(q31q33) and one individual received the derivative chromosome 6 leading to dup (2)(q31q33). The findings associated with the deletion include pre- and postnatal growth retardation, developmental delay, minor facial anomalies, seizures, complex structural heart defects, and limb deficiency. Autopsy of one individual showed complex brain malformations including hydrocephalus secondary to obstruction of the foramina of Monro, extensive heterotopias and polymicrogyria, and an unusual form of total anomalous pulmonary venous return. We compare the findings in these children to those of previously reported cases and construct an overview of the range of anomalies. Apparently, no other individual with dup (2)(q31q33) has been described. We compare the physical peculiarities of our patient with those of individuals with duplications of overlapping regions of 2q.

Glucocorticoid-induced cleft palate (CP) has been used as an animal model for hormonal teratogenesis. In mice, the susceptibility to glucocorticoid-induced CP varies with the strain, A/J being very sensitive and C57/BL6J relatively resistant. Studies in adult and embryonic murine tissues have attempted to correlate the number of glucocorticoid receptors and CP susceptibility, with conflicting results. The relative quantities of dexamethasone receptors were now studied in established palatal and lung fibroblast cell cultures obtained from adult C57 and A/J mice. A rapidly saturable, stable binding system was demonstrated. Scatchard plots were linear indicating a single class of high affinity receptors. The glucocorticoid receptor number ranged from 6.2 x 10(-16) mole/microgram prot to 8.6 x 10(-16) mole/microgram prot, while the KD varied from 1.0 x 10(-8) M to 2.8 x 10(-8) M. The differences in receptor characteristics between murine strains were not significant (p greater than 0.05). The absence of a difference in receptor number between the two strains may reflect the limitation of fibroblast cell culture in assessing glucocorticoid binding in vivo. Alternatively, if a difference in palatal dexamethasone receptor levels between mice strains exists, it may occur only in the embryo.

We report a mother and son with a deletion at 18q22.3. Both have the typical manifestations of the 18q- syndrome. In addition, both have an action tremor which became apparent in childhood. The mother subsequently developed chorea and dysmetria in late adolescence. Magnetic resonance imaging of their brains showed poor myelination of the central white matter tracts with relatively normal myelination of the corpus callosum. We propose that these neurologic findings are most likely due to a failure of expression of the myelin basic protein gene.

Inheritance of a single base mutation in the type III procollagen gene (COL3A1) was studied in a family with aortic aneurysms and easy bruisability. The mutation was a substitution of A for G+ 1 of intron 20 of the gene and caused aberrant splicing of RNA transcribed from the mutated allele. The phenotype in the family included aortic aneurysms that ruptured and produced death. It also included easy bruisability, but it did not include other characteristic features of Ehlers-Danlos syndrome type IV, such as ecchymoses, abnormal scarring, or prominent subcutaneous blood vessels. The data from the family, together with a review of other probands with mutations in the type III procollagen gene, indicated that there is phenotypic overlap between Ehlers-Danlos syndrome type IV and familial arterial aneurysms not associated with any overlap between Ehlers-Danlos syndrome type IV and familial arterial aneurysms not associated with any of the striking changes in skin originally cited as a characteristic feature of Ehlers-Danlos syndrome type IV. In addition, the results suggested that DNA tests for mutations in the type III procollagen gene may be useful to identify individuals predisposed to developing arterial aneurysms.

Neuropathologic examination of two siblings with phenotypic features consistent with Marden-Walker syndrome revealed central nervous system abnormalities which include reduction in the number of spinal anterior horn cells. The occurrence of these changes in a sibling pair provides strong evidence for a genetic etiology. The relationship between the neuropathologic changes and other phenotypic manifestations in this syndrome and in the closely related syndrome of Pena-Shokeir are discussed.

The longitudinal course of two sisters with multiple pterygium syndrome is reported. The findings in these siblings are compared with those of 27 children described in the medical literature. The longitudinal course of short stature, scoliosis, talipes equinovarus, pterygia, hearing loss, and pubertal and intellectual development in this syndrome is described. Recommendations are made for a multidisciplinary approach to individuals with multiple pterygium syndrome, which includes the services of a primary care physician, orthopedist, physical therapist, and plastic surgeon.

The families of 25 probands with sleepwalking and 27 probands with night terrors were studied. Eighty per cent of the sleepwalking pedigrees and 96 per cent of the night terror pedigrees included one or more individuals, other than the proband, who were affected by sleepwalking, night terrors, or both. Our data appear to fit a 'two threshold' multifactorial mode of inheritance. This finding supports the hypothesis that sleepwalking and night terrors share a common genetic predisposition, with sleepwalking being a more prevalent and less severe manifestation of the same substrate that underlies night terrors. Heritable factors predispose an individual to develop sleepwalking and/or night terrors, but expression of the trait may be influenced by environmental factors.

In individuals with mosaicism for trisomy 21, phenotype-karyotype correlations are unpredictable. Two patients are described--one with typical features of Down's syndrome and the other with severe mental retardation only. Both had normal karyotypes in their peripheral lymphocytes but high percentages of trisomic cells in skin fibroblasts.

Del(3)(p25pter) is associated with a characteristic multiple congenital anomalies/mental retardation syndrome. Early recognition of these manifestations and identification of the chromosome defect are essential for proper management and counseling.

N tau-Methylhistidine (MH) and creatinine levels were determined in amniotic fluid and maternal serum from 81 women undergoing midtrimester amniocentesis for reasons other than the diagnosis of neuromuscular disease. Samples were also examined in three pregnancies with male fetuses who were subsequently found to have Duchenne muscular dystrophy (DMD). Between 16 and 20 weeks' gestation, amniotic fluid and maternal serum MH levels averaged 3.22 and 1.94 mumoles/L, respectively. No significant differences were found between the control and affected fetuses for MH and creatinine levels or for MH/creatinine ratios from amniotic fluid or maternal serum. Determination of amniotic fluid MH level thus has no apparent value in the prenatal diagnosis of DMD.

The proband was evaluated at 19 years of age because of primary amenorrhoea and, on chromosomal analysis, was found to have a 46,XY karyotype in 75% of her cells and 48,XY, +8, +21 in 25% of her cells. She appeared normal at birth and exhibited normal intellectual and physical development until puberty when secondary sexual differentiation failed. This young women showed none of the dysmorphic features associated with either trisomy 8 or trisomy 21. Her XY gonadal dysgenesis was manifested by late developmental problems of amenorrhoea, sexual infantilism, and gonadal neoplasia.

A 3-month-old female infant with oral-facial-digital syndrome (OFD-I) was found to have extensive malformations of the brain and spinal cord. Our review of other case reports indicated that the most common central nervous system malformations found in OFD-I include cerebral epithelial (ependymal) cysts, agenesis of the corpus callosum, cerebral micropolygyria, and hypoplasia or dysplasia of the cerebellum, pons, and medulla. It is suggested that the individuals with OFD-I syndrome should be carefully studied clinically and pathologically for complex nervous system anomalies.

We describe 2 sibs with Roberts-SC phocomelia syndrome. Although an ultrasound scan performed at 13 weeks of gestation failed to identify specific abnormalities, repeat scan at 17 weeks detected tetraphocomelia. Ultrasonography can reliably detect Roberts-SC phocomelia prenatally; however, serial scans may be needed. Postmortem examination of the proposita confirmed the sonographic findings and also disclosed dysplastic kidneys and ovarian dysgenesis. The degree of phenotypic variation observed between the sibs supports the hypothesis that Roberts syndrome and SC phocomelia represent a single genetic entity.

The purpose of this study was to determine if encouraging in-depth prenatal genetic counseling before the day of possible genetic amniocentesis affected the use of amniocentesis. Five hundred two patients were referred to our center for prenatal genetic services during a 15-month period. All patients were scheduled for genetic counseling before possible amniocentesis. During the initial three months (group I), patients were routinely scheduled for counseling on the same day of the procedure unless they requested earlier counseling. During the subsequent 12 months (group II), patients were encouraged to undergo counseling before the day of planned amniocentesis, and 48% agreed. When early counseling was encouraged, the use of amniocentesis decreased from 85% (group I) to 73% (group II) (P less than .025). Among patients with advanced maternal age as the only indication for testing (n = 375), utilization of amniocentesis decreased from 93% (group I) to 78% (group II) (P less than .005). A policy of encouraging early prenatal genetic counseling appears to be a significant factor in the use of genetic amniocentesis.

Huntington disease is a progressive neurological disorder with an autosomal dominant mode of inheritance. Using high resolution two-dimensional gel electrophoresis, we analyzed the intracellular and the released protein patterns of skin fibroblasts from HD patients and compared them to cells from apparently normal individuals matched for age and sex. No consistent differences were found in the pattern of total cellular proteins. In contrast, the culture medium from HD patients (12 of 19) contained an Mr 200,000 glycoprotein not found in twelve control cultures. The relation of this protein to the HD gene is unknown.

In a large family with 37 members with multiple exostoses, only one person has developed sarcomatous degeneration of a lesion. Our review of published reports revealed great variation in the incidence of malignancy in multiple exostoses (10 to 25%). Most studies had sampling errors leading to the apparent overstatement of risk. In large pedigrees with essentially complete ascertainment of affected subjects, the risk of malignancy is nearer 3% or less. This lower risk for malignancy may be more appropriate in counselling affected subjects.

A new human endometrial cell line, SCRC-1, has been established from a uterine adenocarcinoma. During a period of 57 weeks in culture, the SCRC-1 cells have been passaged over 100 times. Cultures have an epitheloid morphology, high mitotic activity, and a tendency to form multiple cell layers. The cells are polygonal and are arranged in pavement-like fashion. Most have multiple nucleoli, some are multinucleated, and all have heavily vacuolated cytoplasm. Pretreatment with iododeoxyuridine did not reveal viral markers by cocultivation or immunofluorescence techniques. Karyologic studies indicate that the SCRC11 cell line is essentially diploid with a small subpopulation of tetraploid cells. Over a period of 20 weeks, 1 of 14 athymic nude mice inoculated with SCRC-1 cells developed a tumor which histologically closely resembled the original human tumor. Cells were subsequently propagated from this tumor and the resulting epitheloid-like cell line was designated SCRC-1, Tu 1.

Sibs with virtually identical humero-radial synostosis (HRS) are presented and compared with 17 previously reported cases from the literature of recessively transmitted HRS. The range of anomalies described includes (in addition to humero-radial synostosis) ulnar hypoplasia, patellar hypoplasia, and chronic glomerulo-nephritis.

Rat lung slices and isolated rat lung cells were used to study the secretion of phosphatidylcholine by the lung in vitro. The rate of incorporation of [(3)H]choline by lung slices was 20-fold greater than by liver slices and 4-fold greater in lung cells compared to confluent skin fibroblasts. Labeling lung slices or cells with [(3)H]choline for up to 8 hr failed to reveal a significant amount of labeled phosphatidylcholine in the medium of either system compared to the medium from liver slice or fibroblast controls. Labeling of isolated lung cells for up to 24 hr, with or without 10% fetal calf serum, also showed no significant difference in the amount of labeled phosphatidylcholine in the medium compared to control fibroblast cultures. Washing labeled lung slices or cells with a nonlysing concentration of Triton X-100 (0.05%) did not selectively release labeled phosphatidylcholine, indicating that any secreted phosphatidylcholine did not adhere to the surface of the lung slices or cells. Experiments were performed to determine whether the small amount of phosphatidylcholine in the medium and detergent-released phosphatidylcholine was similar to the tissue and cell phosphatidylcholine. The saturated fatty acid composition of the phosphatidylcholine released by Triton X-100 and in the medium (from lung slices) was identical to that of the tissue phosphatidylcholine. In addition, the relative labeling rates of the phospholipids released by Triton X-100 and in the medium (labeled with [(14)C]glycerol) were identical to those of the tissue and cell phospholipids. Based on these results, we conclude that phosphatidylcholine is not secreted by lung slices and lung cells in large amounts compared to controls. The implication of these data is that pulmonary surfactant material may actually not be secreted by the lung in vitro, and perhaps in vivo, in the manner that is currently generally accepted.

The Fukuyama form of congenital muscular dystrophy (FCMD), first described in Japan, is associated with distinct dysplastic cerebral malformations including agyria and micropolygyria of cerebral cortex, micropolygyria of cerebellum, and leptomeningeal gliomesodermal proliferations. We describe seven cases in four families from the United States with a syndrome similar to FCMD but with additional ophthalmic malformations. We believe that these cases represent a form of congenital muscular dystrophy different from FCMD and termed it cerebro-ocular dysplasia-muscular dystrophy (COD-MD) syndrome.