Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.11.

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.23-q21.1 interstitial deletions in patients. The breakpoints delineate a 500 kb interval within the MAGI2 gene (1.4 Mb in size) that is hemizygously disrupted in 15 of 16 participants with IS or childhood epilepsy, but remains intact in 11 of 12 participants with no seizure history. MAGI2 encodes the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 that interacts with Stargazin, a protein also associated with epilepsy in the stargazer mouse.

Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation.

Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.

Weismann-Netter syndrome and mental retardation: a new patient and review of the literature.

In 1954, Weismann-Netter and Stuhl described three sporadic adults and a mother and her three children with short stature and congenital anterior bowing of lower legs [Weismann-Netter and Stuhl (1954); Presse Méd 62:1618-1622]. They named the condition "toxopachyostéose diaphysaire tibio-péronière," which presently is known as Weismann-Netter syndrome (WNS) (OMIM 112350). Since then more than 100 patients have been published. Nearly all have been case reports in French medical literature, and the first report in the Anglo-American literature appeared in 1988. Only a minority of the publications have appeared during the past two decades. The diagnostic findings of WNS are anterior bowing of the diaphyses of tibia and fibula, broadening or "tibialization" of the fibula and posterior cortical thickening of the two bones. Also the diaphyses of other long bones may be similarly affected but usually to a milder degree. The cause of the condition is unknown, but frequent familial cases suggest a genetic defect with autosomal dominant inheritance. Several of the WNS patients have also had mental retardation (MR), but the existence of a WNS-MR syndrome is still pending. We describe a sporadic patient with typical WNS skeletal findings and MR. He also had postnatal growth deceleration with partially corrective pubertal growth, normal head size and normal brain structures on MRI. We review the WNS literature.

Further evidence for a relationship between the 5p15 chromosome region and the oculoauriculovertebral anomaly.

The oculoauriculovertebral anomaly (OAV) or Goldenhar syndrome is a malformation complex that has been described in several chromosomal rearrangements. Among them a deletion of the terminal 5p has recurred in seven previous patients. We wish to report on an additional such patient in order to reinforce the significance of this genomic region in the cause of at least a subgroup of OAV cases. Future studies, particularly in the OAV patients with a lateral facial cleft, might define one genetic background of the disorder. Our patient had a complex translocation chromosome 45,XX, inv(2) (q32q37)mat, dic(5;21) (p15.3;q22.3)dn, resulting in a terminal 5p deletion, a terminal deletion of 21q demonstrated by FISH studies, and a duplication of 21q22.11-q22.12 documented by molecular karyotyping. In addition to OAV she developed myelodysplasia treated with bone marrow transplantation. We discuss her clinical findings with reference to her karyotype findings and review the patients with OAV and a terminal deletion of 5p.

Molecular karyotyping in patients with mental retardation using 100K single-nucleotide polymorphism arrays.

BACKGROUND: Using array techniques, it was recently shown that about 10% of patients with mental retardation of unknown origin harbour cryptic chromosomal aneusomies. However, data analysis is currently not standardised and little is known about its sensitivity and specificity. METHODS: We have developed an electronic data analysis tool for gene-mapping SNP arrays, a software tool that we call Copy Number Variation Finder (CNVF). Using CNVF, we analysed 104 unselected patients with mental retardation of unknown origin with a genechip mapping 100K SNP array and established an optimised set of analysis parameters. RESULTS: We detected deletions as small as 20 kb when covered by at least three single-nucleotide polymorphisms (SNPs) and duplications as small as 150 kb when covered by at least six SNPs, with only one false-positive signal in six patients. In 9.1% of patients, we detected apparently disease-causing or de novo aberrations ranging in size from 0.4 to 14 Mb. Morphological anomalies in patients with de novo aberrations were equal to that of unselected patients when measured with de Vries score. CONCLUSION: Our standardised CNVF data analysis tool is easy to use and has high sensitivity and specificity. As some genomic regions are covered more densely than others, the genome-wide resolution of the 100K array is about 400-500 kb for deletions and 900-1000 kb for duplications. The detection rate of about 10% of de novo aberrations is independent of selection of patients for particular features. The incidental finding in two patients of heterozygosity for the 250 kb recurrent deletion at the NPH1 locus, associated with autosomal recessive juvenile nephronophthisis, which was inherited from a healthy parent, highlights the fact that inherited aberrations might be disease-related even though not causal for mental retardation.

Clinical and mutational spectrum of Mowat-Wilson syndrome.

Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.

Temporo-occipital spikes: a typical EEG finding in Kabuki syndrome.

Kabuki syndrome is a rare dysmorphogenic disorder. The central nervous system is often involved, and epilepsy is a common symptom. The diagnosis is clinical, and no typical electroencephalographic findings have thus far been reported. We have documented temporo-occipital spikes in sleep electroencephalogram in all our three Kabuki patients. The location of the spikes was similar in all cases although their occurrence varied from continuous spiking to single spikes. We suggest that temporo-occipital spikes are typical in Kabuki syndrome and discuss the possible cause of this finding.

Dysmorphic facial features in aspartylglucosaminuria patients and carriers.

The facial photos of 76 aspartylglucosaminuria (AGU) patients, 29 obligate carriers and 78 unrelated controls were evaluated for dysmorphic features to see whether this autosomal recessive lysosomal storage disease includes a dysmorphic facial gestalt in addition to the well-known age-related coarsening of the facies and whether the carrier status of AGU might have an effect on the facial features. A consistent dysmorphic gestalt with hypertelorism, a short and broad nose with round nares, simple often small ears with small or missing lobule and modest folding of helices, thick lips and a square shape of face, was found to be present long before the coarsening begins. Recognition of this pattern of facial features might help in the early diagnosis of AGU. Statistically, puffy eyelids were found to be significantly more frequent in AGU carriers than in controls. These findings support an earlier implication that AGU carrier status might have a slight influence on the phenotype.

Hypertrichosis, hyperkeratosis, abnormal corpus callosum, mental retardation and dysmorphic features in three unrelated females.

We report three unrelated patients with hypertrichosis, mild to moderate mental retardation, and dysmorphic facial features including low anterior hairline, thick arched eyebrows, nose with broad tip and columella below alae nasi, short philtrum, thick drooping lower lip and simple posteriorly rotated ears. They also had rough skin with hyperkeratotic plaques. Feet and finger tips were broad. All of them had personality problems like aggressiveness, stubborn temperament or tendency to withdraw. Brain MRI showed thick and short corpus callosum. We believe that these patients represent a new syndrome of unknown aetiology.

X-exome sequencing in Finnish families with intellectual disability--four novel mutations and two novel syndromic phenotypes.

BACKGROUND: X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis. METHODS & OBJECTIVES: Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause. RESULTS: We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype. CONCLUSIONS: All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations and the challenges of interpreting the results. Further functional studies are required to confirm the cause of the syndromic phenotypes associated with ZMYM3 and SYP in this study.

Translation of a research-based genetic test on a rare syndrome into clinical service testing, with sotos syndrome as an example.

BACKGROUND AND AIMS: It is often the case that the genetic background of a rare disease has been solved, but the testing of a clinical patient can be performed only through research projects. Translating a research-based test into diagnostic service may also appear laborious and costly. Based on our molecular research of the genetics of Sotos syndrome, we developed a clinical laboratory test that is both effective and relatively inexpensive. METHODS AND RESULTS: Pilot testing was performed with samples of clinically diagnosed Sotos cases (n=13), and testing was continued with samples of patients who were suspected of having Sotos syndrome (n=161). The testing methods used were direct sequencing and multiplex ligation-dependent probe amplification. Sotos syndrome was a suitable example for test translation, because its genetic background was well established, and the demand for the test was expected to be fairly high. In the pilot phase, a mutation was detected in 12 out of 13 patients (92%), and in the second group, 49 out of 161 (30%) patients had a mutation in the NSD1 gene. CONCLUSIONS: In Sotos syndrome, detecting the mutation is valuable for the patient/family, while the value of a negative result is less clear and other differential diagnostic diagnoses should be considered. For successful translation of the research-based test into routine diagnostics, intense collaboration between clinicians, researchers, and diagnostic laboratory personnel is essential.

9q22 Deletion--first familial case.

BACKGROUND: Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400) due to haploinsufficiency of the PTCH1 gene (MIM *601309). METHODS AND RESULTS: We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K). The deletion does not involve the PTCH1 gene, but instead 30 other gene,s including the ROR2 gene (MIM *602337) which causing both brachydactyly type 1 (MIM #113000) and Robinow syndrome (MIM #268310), and the immunologically active SYK gene (MIM *600085). The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations. CONCLUSIONS: This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling.

De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome.

Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.

PAK3 related mental disability: further characterization of the phenotype.

We report clinical, neuropsychological and molecular findings in affected males and carrier females in the fourth reported family with mental retardation caused by mutation in the PAK3 gene (Xq22.3-q23), W446S. In contrast to previous reports, carrier females manifested learning problems and mild mental disability. Skewed X-inactivation was observed here for the first time in carriers of PAK3 mutation. Neuropsychological tests in affected males and carrier females suggested a common neuropsychological profile of impaired spatial cognitive abilities and defects in attentional and executive functions. The five affected males examined herein had a proportionally small head size or microcephaly, large ears, oral motor hypotonia with drooling and inarticulate speech and short attention span, anxiety, restlessness, and aggression. Brain imaging showed signs of chronic non-progressive hydrocephalus in one patient who manifested psychosis and fluctuant gait deterioration, while two other patients showed no abnormalities. EEG recordings were available from four affected males and one carrier female, and all showed similar posterior slow wave activity without epileptic discharges. Only one affected male in the family suffered from epilepsy. When comparing the affected males in this family and the three previously reported families with mental retardation due to a PAK3 mutation, similarities in their characteristics were small head size or microcephaly, large ears, speech defects, behavioral abnormalities, and psychiatric disease.

Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).

Pitt-Hopkins syndrome is a rarely reported syndrome of so-far-unknown etiology characterized by mental retardation, wide mouth, and intermittent hyperventilation. By molecular karyotyping with GeneChip Human Mapping 100K SNP arrays, we detected a 1.2-Mb deletion on 18q21.2 in one patient. Sequencing of the TCF4 transcription factor gene, which is contained in the deletion region, in 30 patients with significant phenotypic overlap revealed heterozygous stop, splice, and missense mutations in five further patients with severe mental retardation and remarkable facial resemblance. Thus, we establish the Pitt-Hopkins syndrome as a distinct but probably heterogeneous entity caused by autosomal dominant de novo mutations in TCF4. Because of its phenotypic overlap, Pitt-Hopkins syndrome evolves as an important differential diagnosis to Angelman and Rett syndromes. Both null and missense mutations impaired the interaction of TCF4 with ASCL1 from the PHOX-RET pathway in transactivating an E box-containing reporter construct; therefore, hyperventilation and Hirschsprung disease in patients with Pitt-Hopkins syndrome might be explained by altered development of noradrenergic derivatives.

Pitt-Hopkins syndrome in two patients and further definition of the phenotype.

Pitt-Hopkins syndrome is a rare dysmorphic mental retardation syndrome marked by daytime spells of overbreathing interrupted by apnoea. The dysmorphism consists of a large beaked nose, cup-shaped ears with broad helices, a wide mouth, Cupid's bow upper lip, wide and shallow palate and broad or clubbed fingertips. The four patients described so far have been sporadic and represented both sexes. In addition, a pair of sibs with atypical features has been reported as possible Pitt-Hopkins syndrome cases. We describe two unrelated Pitt-Hopkins syndrome patients in order to further define the phenotype. In addition to severe developmental retardation, hypotonia, postnatal growth retardation, microcephaly, abnormal breathing and characteristic dysmorphic features, both had epilepsy and intestinal problems with severe constipation in one and Hirschsprung disease in the other. Other abnormalities were hypopigmented skin macules in one and high-grade myopia in the other. Both had unusual frontal slow-and-sharp-wave discharges on electroencephalography. Magnetic resonance imaging in both showed a similar hypoplastic corpus callosum with missing rostrum and posterior part of the splenium and bulbous caudate nuclei bulging towards the frontal horns. Chromosomal analysis and subtelomere fluorescence in-situ hybridization studies were normal. No mutations were found in the MECP2 or ZFHX1B genes. Extensive metabolic and mitochondrial screens were normal. The electroencephalography and brain magnetic resonance imaging findings appear to be further diagnostic signs in Pitt-Hopkins syndrome, which is also one of the syndromes associated with Hirschsprung disease.

The first Finnish patient with the Floating-Harbor syndrome: the follow-up of eight years.

We report the follow-up data on the first Finnish patient with the Floating-Harbor syndrome (FHS) reported by us in 1996 at the age of 6 years (Ala-Mello and Peippo. We also discuss the diagnostic criteria of FHS, with a critical review of the literature.