Susan Zeesman

Absence of a Paternally Inherited FOXP2 Gene in Developmental Verbal Dyspraxia

Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.

Ovarian Failure Related to Eukaryotic Initiation Factor 2B Mutations

Ovarian failure (OF) at age <40 years occurs in approximately 1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. We studied eight patients who presented with premature OF and white-matter abnormalities on magnetic resonance imaging. Neurological signs may be absent or present after OF. In seven patients, we report for the first time mutations in three of the five EIF2B genes (EIF2B2, -4, and -5) that were recently shown to cause childhood ataxia with central nervous system hypomyelination/vanishing white-matter disease leukodystrophy. The correlation we observed between the age at onset of the neurological deterioration and the severity of OF suggests a common pathophysiological pathway.

Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2

We report detailed clinical, cytogenetic, and molecular findings in a girl with a deletion of chromosome 7q31‐q32. This child has a severe communication disorder with evidence of oromotor dyspraxia, dysmorphic features, and mild developmental delay. She is unable to cough, sneeze, or laugh spontaneously. Her deletion is on the paternally inherited chromosome and includes the FOXP2 gene, which has recently been associated with speech and language impairment and a similar form of oromotor dyspraxia in at least three other published cases. We hypothesize that our patients communication disorder and oromotor deficiency are due to haploinsufficiency for FOXP2 and that her dysmorphism and developmental delay are a consequence of the absence of the other genes involved in the microdeletion. We propose that this patient, together with others reported in the literature, may define a new contiguous gene deletion syndrome encompassing the 7q31‐FOXP2 region. Cytogenetic and molecular analysis of this region should be considered for other individuals displaying similar characteristics.

Paternal transmission of fragile X syndrome.

We present a family in which a fragile X mosaic male, who carries both premutation and full mutation alleles in his peripheral blood leukocytes, has a daughter with both premutation and partially methylated full mutation alleles and a significant developmental disability. To our knowledge, this is the first report of such an occurrence and it challenges current thinking about the expansion and transmission of unstable FMR1 alleles from men to their daughters. It is currently accepted that neither males with premutations nor full mutations are at risk for having daughters with full mutations and fragile X syndrome. The sperm cells of full mutation males are thought to carry only premutation alleles. These alleles, when transmitted through a male, regardless of his cognitive status, are thought to be unable to expand to full mutations in the next generation. In effect, the expansion from premutation to full mutation has only been observed through female meioses. The sperm cells in the father in this family have been shown to contain only alleles in the premutation range. Since his daughter has both premutation and full mutation alleles the expansion to full mutation in this case must have occurred postzygotically.

Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A

Purpose:A number of genes in the 9q34.11 region may be haploinsufficient. However, studies analyzing genotype–phenotype correlations of deletions encompassing multiple dosage-sensitive genes in the region are lacking.Methods:We mapped breakpoints of 10 patients with 9q34.11 deletions using high-resolution 9q34-specific array comparative genomic hybridization (CGH) to determine deletion size and gene content.Results:The 9q34.11 deletions range in size from 67 kb to 2.8 Mb. Six patients exhibit intellectual disability and share a common deleted region including STXBP1; four manifest variable epilepsy. In five subjects, deletions include SPTAN1, previously associated with early infantile epileptic encephalopathy, infantile spasms, intellectual disability, and hypomyelination. In four patients, the deletion includes endoglin (ENG), causative of hereditary hemorrhagic telangiectasia. Finally, in four patients, deletions involve TOR1A, of which molecular defects lead to early-onset primary dystonia. Ninety-four other RefSeq genes also map to the genomic intervals investigated.Conclusion:STXBP1 haploinsufficiency results in progressive encephalopathy characterized by intellectual disability and may be accompanied by epilepsy, movement disorders, and autism. We propose that 9q34.11 genomic deletions involving ENG, TOR1A, STXBP1, and SPTAN1 are responsible for multisystemic vascular dysplasia, early-onset primary dystonia, epilepsy, and intellectual disability, therefore revealing cis-genetic effects leading to complex phenotypes.Genet Med 2012:14(10):868–876

Duplication of AKT3 as a cause of macrocephaly in duplication 1q43q44.

Somatic and germline duplications of AKT3 and activating mutations of this gene have been reported in individuals with megalencephaly and hemimegalencephaly. We report on a patient with macrocephaly and a 3 Mb duplication on 1q43q44 that includes AKT3. This duplication was detected by array comparative genomic hybridization. The patient presented with moderate developmental delays in gross motor movements and speech. She also had macrocephaly, frontal bossing, hypertelorism, wide nasal bridge, small alae nares, short philtrum, prominent upper lip, and low‐set, protruding ears. The 3 Mb duplicated region contained 15 genes including AKT3. The observation of megalencephaly in a child with 1q43q44 duplication provides further evidence of involvement of AKT3 dosage imbalances in brain growth disturbance.

Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

Purpose:Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis.Methods:In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization.Results:Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5′ MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain.Conclusion:Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460–466.

Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression

Purpose:The purpose of the current study was to assess the penetrance of NRXN1 deletions.Methods:We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions.Results:We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91–22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3ʹ end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5ʹ NRXN1 deletion (OR = 7.47; 95% CI: 2.36–23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035).Conclusions:The results support the importance of exons near the 5ʹ end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53–61.

Oral-facial-digital syndrome VII is oral-facial-digital syndrome I: a clarification.

We report on further clinical findings in the one single family in the literature classified as oral‐facial‐digital (OFD) type VII in order to demonstrate that the diagnosis in this kindred should, in fact, be OFD type I. The mother and the daughter described in the original report have since developed polycystic kidney disease. In addition, the daughter recently had a daughter of her own with central nervous system, oral and digital anomalies. Linkage studies have shown that all the affected women share the same haplotype across the previously identified region Xp22.2p22.3 to which OFD I maps. Although the pedigree was too small for a significant lod score, the combination of clinical and molecular information clearly shows that the disease in this family is OFD I. We report this family in order to clarify and simplify the classification of the oral‐facial‐digital syndrome spectrum and to recommend the removal of OFD VII from the classification system of the oral‐facial‐digital syndromes.

Pregnancy in a healthy woman with untreated citrullinemia

We report the clinical and biochemical data on a second successful pregnancy in a woman with citrullinemia due to argininosuccinate synthetase deficiency (CTLN1). Despite very elevated plasma and urine citrulline and little or no measurable argininosuccinate synthetase enzyme activity on cultured skin fibroblasts, this 29‐year‐old woman, who was identified through newborn screening, has remained asymptomatic throughout her life. Mutation analysis has recently revealed that she is a compound heterozygote for a known and a novel mutation (IVS15‐1G > C and K310Q, respectively). Many newborn screening programs have recently been expanded to include citrullinemia and numerous asymptomatic hypercitrullinemic infants and children have been identified. It is now important to define prognostic indicators that will help with treatment decisions and genetic counseling for these patients. This patient, as the only citrullinemic adult who has been followed prospectively, contributes important information in this regard. In addition, her child was unaffected by the high citrulline levels demonstrated in amniotic fluid and breast milk suggesting that citrulline is not teratogenic. Although pregnancy is an important risk factor for women with CTLN1, it appears that females with citrullinemia can have normal pregnancy outcomes, as long as metabolic crisis is avoided.