Blended phenotype of combination of HERC2 and AP3B2 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15.

Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disability (ID), a distinctive gait pattern, abnormal behaviors, severe impairment in language development, and characteristic facial features. Most cases are caused by the absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Here, we present the first reported case of a 3-year-old boy with an atypical phenotype of Angelman syndrome due to uniparental isodisomy with two recessive homozygous pathogenic variants: in HERC2 and AP3B2. Known phenotypes related to HERC2 and AP3B2 include ID and early infantile epileptic encephalopathy, respectively. The patient had severe global developmental delay and profound ID and showed a happy demeanor, stereotypic laughter, and hand-flapping movements, but also irritability. Craniofacial dysmorphic features, including brachycephaly, strabismus, wide ala nasi, short philtrum, wide open mouth, and slight hypopigmentation were seen. Progressive microcephaly was noted. Magnetic resonance imaging of the brain showed delayed myelination and cerebral atrophy. Trio whole exome sequencing and CGH-SNP array analysis revealed paternal uniparental isodisomy of chromosome 15 and two coexisting recessive diseases resulting from homozygous HERC2 and AP3B2 pathogenic variants. The pathogenic variant in HERC2 was inherited from his heterozygous-carrier father, and the variant in AP3B2 was de novo. We suppose that these unusual features were the combination of the effect of three concomitant disorders.

Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.

Jalili syndrome is a rare multisystem disorder with the most prominent features consisting of cone-rod dystrophy and amelogenesis imperfecta. Few cases have been reported in the Americas. Here we describe a case series of patients with Jalili syndrome examined at the National Eye Institute's Ophthalmic Genetics clinic between 2016 and 2018. Three unrelated sporadic cases were systematically evaluated for ocular phenotype and determined to have cone-rod dystrophy with bull's eye maculopathy, photophobia, and nystagmus. All patients had amelogenesis imperfecta. Two of these patients had Guatemalan ancestry and the same novel homozygous CNNM4 variant (p.Arg236Trp c.706C > T) without evidence of consanguinity. This variant met likely pathogenic criteria by the American College of Medical Genetics guidelines. An additional patient had a homozygous deleterious variant in CNNM4 (c.279delC p.Phe93Leufs*31), which resulted from paternal uniparental isodisomy for chromosome 2p22-2q37. This individual had additional syndromic features including developmental delay and spastic diplegia, likely related to mutations at other loci. Our work highlights the genotypic variability of Jalili syndrome and expands the genotypic spectrum of this condition by describing the first series of patients seen in the United States.

Cardiac Failure in a Trisomy 9 Patient Undergoing Anesthesia: A Case Report.

A 27-year-old female with Trisomy 9 mosaicism presented to Children's Hospital Colorado for outpatient dental surgery under general anesthesia. The patient's past medical history was also significant for premature birth, gastroesophageal reflux, scoliosis and kyphosis, obesity, and developmental delay. Per her mother's report, the patient had no cardiac issues. She had undergone multiple previous general anesthetics, some of which documented respiratory complications such as laryngospasm, bronchospasm, and possible aspiration. During this anesthetic, the patient became hypotensive on induction, with sluggish response to intravenous fluids, glycopyrrolate, and ephedrine. Her electrocardiogram demonstrated what appeared to be left bundle branch block at baseline, with possible ST segment changes after induction. Due to her abnormal reaction to the induction and subsequent treatment for hypotension, an echocardiogram was performed. The patient was found to have an ejection fraction of 25%-30%. The anesthetic was uneventful for the remainder of the procedure, and following recovery, the patient was admitted by the heart failure team for further care.

Angelman syndrome in adulthood.

Angelman syndrome (AS) is a neurogenetic disorder. The goal of this study was to investigate the primary health issues affecting adults with AS and to further characterize the natural history and genotype-phenotype correlations. Standardized phone interviews with caregivers for 110 adolescents and adults with AS were conducted. The impact of age, sex, and genotype on specific outcomes in neurology, orthopedics, internal medicine, and psychiatry were investigated. The mean age of individuals with AS was 24 years (range 16-50y). Active seizures were present in 41% of individuals, and 72% had sleep dysfunction. Significant constipation was present in 85%, and 32% were overweight or obese, with obesity disproportionately affecting women. Scoliosis affected 50% with a mean age at diagnosis of 12 years, and 24% of those diagnosed with scoliosis required surgery, an intervention disproportionately affecting men. Sixty-eight percent were able to walk independently, and 13% were able to speak 5 or more words. Self-injurious behavior was exhibited in 52% of individuals. The results of this study indicate that epilepsy severity may assume a bimodal age distribution: seizures are typically most severe in early childhood but may recur in adulthood. While late-adolescent and adult sleep patterns were improved when compared to the degree of sleep dysfunction present during infancy and childhood, the prevalence of poor sleep in adults remained quite high. Primary areas of clinical management identified include the following: seizures, sleep, aspiration risk, GERD, constipation, dental care, vision, obesity, scoliosis, bone density, mobility, communication, behavior, and anxiety.

Transforming growth factor-alfa gene (TGFA), human tooth agenesis, and evidence of segmental uniparental isodisomy.

We have previously reported an association between variants in the transforming growth factor-alfa gene (TGFA) and human tooth agenesis. To demonstrate in greater detail that TGFA contributes to tooth agenesis, we investigated additional markers in the gene. Cheek swab samples were obtained for DNA analysis from 116 patient/parent trios. Probands had at least one developmentally missing tooth, excluding third molars. Genotyping was performed using TaqMan assays. Linkage disequilibrium analysis and test of the transmission distortion of the marker alleles were performed. We confirmed that TGFA variants and haplotypes are associated with tooth agenesis. Moreover, it appears that preferential premolar agenesis is associated with TGFA, and patients with a family history of tooth agenesis would have an associated haplotype. Finally, we excluded that a TGFA microdeletion could cause sporadic agenesis in a case of upper lateral incisors and lower second premolars and suggest this case may be consequence of a segmental uniparental isodisomy.

Beckwith-Wiedemann syndrome with asymmetric mosaic of paternal disomy causing hemihyperplasia.

Beckwith-Wiedemann syndrome (BWS) is a congenital disorder with 3 main features-overgrowth in infancy, macroglossia, and abdominal wall defects. Here, we report on a 5-month old girl with hemihyperplasia and macroglossia caused by paternal uniparental disomy (pUPD) asymmetric mosaic on chromosome 11p15.5. She could not retract her tongue into her mouth and the midline of the tongue was shifted to the left. Glossectomy was performed at age 1 year. A specimen of the tongue showed normal skeletal muscle, but the muscle fibers were closely spaced, and there were fewer stroma components in the tissue from the right side of the tongue than that from the left side. With respect to pUPD of chromosome 11p15.5, microsatellite marker analysis of the tongue tissue specimen revealed a higher mosaic rate in the tissue from the right side of the tongue (average 48.3%) than that from the left side (average 16.9%). Methylation analysis of Kv differentially methylated region (DMR) 1 (KvDMR1) and H19DMR revealed hypomethylation of KvDMR1 and hypermethylation of H19DMR in the tissue on the right side of the tongue (hyperplastic side). In this case, the difference in mosaic rate of pUPD in the 11p15.5 region was hypothesized to influence the expression level of insulin-like growth factor 2. This result may be helpful to clinicians, especially surgeons, when planning plastic surgery for hemihyperplasia.

Angelman syndrome: a review of the clinical and genetic aspects.

Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe learning difficulties, ataxia, a seizure disorder with a characteristic EEG, subtle dysmorphic facial features, and a happy, sociable disposition. Most children present with delay in developmental milestones and slowing of head growth during the first year of life. In the majority of cases speech does not develop. Patients with AS have a characteristic behavioural phenotype with jerky movements, frequent and sometimes inappropriate laughter, a love of water, and sleep disorder. The facial features are subtle and include a wide, smiling mouth, prominent chin, and deep set eyes. It is caused by a variety of genetic abnormalities involving the chromosome 15q11-13 region, which is subject to genomic imprinting. These include maternal deletion, paternal uniparental disomy, imprinting defects, and point mutations or small deletions within the UBE3A gene, which lies within this region. UBE3A shows tissue specific imprinting, being expressed exclusively from the maternal allele in brain. The genetic mechanisms identified so far in AS are found in 85-90% of those with the clinical phenotype and all interfere with UBE3A expression.

Severe hemihypotrophy in a female infant with mosaic Turner syndrome: a variant of Russell-Silver syndrome?

Russell-Silver syndrome is a genetically heterogeneous condition. For most affected individuals, it represents a phenotype rather than a specific disorder. Although chromosomal anomalies, imprinting disorder, maternal uniparental disomy 7 as well as familial autosomal dominant and X-linked forms have been reported, the diagnosis remains determined on clinical grounds. Russell-Silver syndrome is characterized by asymmetric intrauterine growth retardation, postnatal failure to thrive, distinct facial features, limb asymmetry, excessive sweating and minor skin lesions. We report here a female infant who had a karyotype of 45,X on prenatal amniocytes. After delivery she was noted to have features not explainable on the basis of Turner syndrome. Her phenotype actually was quite consistent with Russell-Silver syndrome. She had a triangular face with prominent forehead, large eyes, a thin nose, malar hypoplasia, thin upper lip with down-turned corner of the mouth and a pointed chin. Marked body asymmetry was evident at birth, with the left side significantly smaller than the right side. She has a diphalangeal left fifth finger. Skin fibroblast culture and analysis showed a karyotype of 45,X on the right side and 45,X/46,XX on the left side. The case is another illustration of the genetic heterogeneity of Russell-Silver phenotype.

Partial trisomy 8 mosaicism not detected by cultured amniotic-fluid cells.

OBJECTIVE: Prenatal detection of trisomy 8 mosaicism can be misleading and remains challenging in genetic counseling. Identifying cases of partial or complete trisomy 8 mosaicism will highlight the pitfalls of conventional karyotyping in prenatal amniocentesis for partial or complete trisomy 8 mosaicism. CASE REPORT: The patient was born uneventfully at term to a healthy 34-year-old mother. Analysis of the amniotic fluid (AF) cells showed a normal male karyotype. At birth, the newborn presented dysmorphic features, including asymmetric mandibles and ears, anteverted nostrils with a relatively long philtrum, retrognathia, and a clenched hand on the left side. Imaging studies revealed agenesis of the corpus callosum with bilateral colpocephaly, a common arterial trunk bifurcating into the left subclavian and carotid arteries, and bilateral pelviectasis. Cytogenetic analysis of the blood revealed mosaicism of partial trisomy 8: 47,XY,+del(8) (q21.3) [8]/46,XY [12]. Array comparative genomic hybridization (array-CGH) revealed 82.9 Mb duplications at chromosome 8p23.3-8q21.3 with dosage variations. Interphase fluorescence in situ hybridization analysis of urine sediments and buccal smears were compatible with mosaic compositions. A small colony of AF cells was found to have partial trisomy 8 in repeated analysis. CONCLUSION: Conventional karyotyping through amniocentesis has limitations particularly in detecting rare trisomy mosaicism if trisomic cells show growth disadvantage. Array-CGH using uncultured cells may be of help in providing more information on genetic dosage variations in such cases.

Trisomy 10 mosaicism and maternal uniparental disomy 10 in a liveborn infant with severe congenital malformations.

We report on a liveborn infant with trisomy 10 mosaicism combined with maternal uniparental heterodisomy for chromosome 10. The mosaicism 47,XY,+10/46,XY was found in five different tissues, including one blood sample, while cultured lymphocytes from two other blood samples showed a normal karyotype, 46,XY. DNA analysis with six PCR-based microsatellite markers demonstrated the trisomic cell line to be a result of maternal meiotic nondisjunction, and revealed maternal uniparental heterodisomy in the diploid cell line, suggesting that the formation of the diploid cell line was due to trisomy rescue. The boy had severe growth retardation, major dysmorphism, and malformations, and died at 37 days. We reviewed the previous nine reports of infants and fetuses with trisomy 10 mosaicism reported in the literature. We suggest that a common clinical syndrome can be defined comprising skull, jaw and ear abnormalities, cleft lip/palate, malformations of eyes, heart and kidneys, deformity of hands and feet, and most often death neonatally or in early infancy. The cytogenetic findings in the present patient demonstrate the importance of karyotyping more than one tissue, and not only lymphocytes, when a chromosomal aberration is strongly suspected.

Phenotypic and behavioral variability within Angelman Syndrome group with UPD

The Angelman syndrome (AS) (developmental delay, mental retardation, speech impairment, ataxia, outbursts of laughter, seizures) can result either from a 15q11-q13 deletion, or from paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. We describe here the phenotypic and behavioral variability detected in eight UPD patients out of a group of 58 AS patients studied. All of them presented developmental delay, mental retardation, ataxia, speech impairment, and frequent drooling. Only one had microcephaly, whereas in two of them the OFC (head circumference) was above the 98th percentile. The weight of all patients was above the 50th percentile, and in three of them the height was above the 90th percentile. Three were able to say a few words and to communicate by gestures. Two patients presented hyperphagia, and three presented skin picking, common features in the Prader-Willi syndrome (PWS). Four patients (4/7) had wide-spaced teeth. Five presented seizures, and two others did not manifest frequent laughter. One patient was very different from the others, as he showed a better understanding and abilities to communicate, to play video games and to draw. We suggest here that there seems to be an extreme phenotypic and behavioral variability within the UPD group, and that both typical patients and those with mental retardation, language impairment, happy disposition, and hyperactivity should be tested for AS