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Background: Inherited glycosylphosphatidylinositol (GPI) deficiency is an autosomal recessive disease and a set of syndromes caused by different genes involved in the biosynthesis of phosphatidylinositol characterized by severe cognitive disability, elevated serum alkaline phosphatase (ALP) levels, and distinct facial features. This report presents a patient with inherited GPI deficiency caused by a homozygous frameshift variant of PGAP3 due to uniparental isodisomy (UPiD) on chromosome 17. Method: Clinical characteristics of the patient were collected. Microarray analysis followed by adaptive sampling sequencing targeting chromosome 17 was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. Results: The patient was born at 38 weeks of gestation with a birthweight of 3893 g. He had a distinctive facial appearance with hypertelorism, wide nasal bridge, and cleft soft palate. Postnatal head magnetic resonance imaging revealed a Blake's pouch cyst. The serum ALP level was 940 IU/L at birth and increased to 1781 IU/L at 28 days of age. Microarray analysis revealed region of homozygosity in nearly the entire region of chromosome 17, leading to the diagnosis of UPiD. Adaptive sampling sequencing targeting chromosome 17 confirmed the homozygous variant NM_033419:c.778dupG (p.Val260Glyfs*14) in the PGAP3 gene, resulting in a diagnosis of inherited GPI deficiency. Conclusion: This is the first report of inherited GPI deficiency caused by UPiD. Inherited GPI deficiency must be considered in patients with unexplained hyperphosphatasemia. [ABSTRACT FROM AUTHOR]

WOREE syndrome is an early infantile epileptic encephalopathy characterized by drug‐resistant seizures and severe psychomotor developmental delays. We report a case of a WWOX splice‐site mutation with uniparental isodisomy. A 1‐year and 7‐month‐old girl presented with nystagmus and epileptic seizures from early infancy, with no fixation or pursuit of vision. Physical examination revealed small deformities, such as swelling of both cheeks, folded fingers, rocking feet, and scoliosis. Brain imaging revealed slight hypoplasia of the cerebrum. Electroencephalogram showed focal paroxysmal discharges during the interictal phase of seizures. Vitamin B6 and zonisamide were administered for early infantile epileptic encephalopathy; however, the seizures were not relieved. Despite altering the type and dosage of antiepileptic drugs and ACTH therapy, the seizures were intractable. Whole‐exome analysis revealed the homozygosity of WWOX(NM_016373.4):c.516+1G>A. The WWOX mRNA sequencing using peripheral blood RNA confirmed that exon 5 was homozygously deleted. Based on these results, the patient was diagnosed with WOREE syndrome at 5 months. The WWOX variant found in this study is novel and has never been reported before. WOREE syndrome being extremely rare, further case series and analyses of its pathophysiology are warranted. [ABSTRACT FROM AUTHOR]

TRAPPC9 loss‐of‐function biallelic variants are associated with an autosomal recessive intellectual disability syndrome (Online Mendelian Inheritance of Man no. 613192), also characterized by microcephaly, hypertelorism, obesity, growth delay, and behavioral differences. Here, we describe an 8‐year‐old Hispanic female with neurodevelopmental disorder, partial epilepsy, microcephaly, bilateral cleft lip and alveolus, growth delay, and dysmorphic features. She had abnormal myelination, mega cisterna magna, and colpocephaly on brain magnetic resonance imaging (MRI). Microarray showed a single ~146 Mb region of homozygosity (ROH) encompassing all of Chromosome 8, consistent with uniparental isodisomy (UPD). Exome sequencing performed in‐house did not identify single nucleotide variants to explain her phenotype. Algorithms developed in‐house and further evaluation of BAM files revealed a homozygous deletion overlapping Exon 2 in TRAPPC9 within the ROH. Subsequent del/dup analyses with exon‐level oligo array confirmed a likely pathogenic deletion in TRAPPC9 (NM_031466.5): arr[GRCh37] 8q24.3(141460661_141461780)x0. Our case highlights the implications of downstream analyses from UPD/ROH given the increased risk for AR conditions, the strengths of combining orthologous molecular methods to establish a diagnosis and further delineates the TRAPPC9‐related phenotype in an individual of Hispanic ancestry. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss, gastrointestinal abnormalities, and absent salivation. Next‐generation sequencing revealed a uniparental isodisomy in chromosome 5, and a 22 kb homozygous deletion in SLC12A2, which encodes for sodium, potassium, and chloride transporter in the basolateral membrane of secretory epithelia. Functional studies using patient‐derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein abundance when compared with control. Loss of Slc12a2 in mice has been shown to lead to deafness, abnormal neuronal growth and migration, severe gastrointestinal abnormalities, and absent salivation. Together with the described phenotype of the Slc12a2‐knockout mouse model, our results suggest that the absence of functional SLC12A2 causes a new genetic syndrome and is crucial for the development of auditory, neurologic, and gastrointestinal tissues. [ABSTRACT FROM AUTHOR]

TBC1D24‐related disorders are rare neurodevelopmental disorders that show a broad range of neuropsychiatric deficits and are mostly inherited in an autosomal recessive manner. Here we describe a case with early‐onset epileptic encephalopathy, in whom exome sequencing detected a novel pathogenic homozygous c.442G>A, p.(Glu148Lys) variant in TBC1D24. She showed severe developmental delay, congenital sensorineural hearing loss and seizures, but the combination of a high dose phenobarbital and potassium bromide was very effective for the seizures. Sanger sequencing revealed that her mother was a heterozygous carrier of the TBC1D24 variant, but her father showed only wild‐type alleles. Homozygosity mapping analysis using exome data showed loss of the heterozygosity region at 16p13.3–p13.13 encompassing TBC1D24. Genotyping analysis using rare variants within loss of the heterozygosity region indicated that the patient has a homozygous haplotype inherited from her mother, indicating maternal segmental uniparental isodisomy (UPiD). These data clearly show that exome sequencing is a powerful tool to perform comprehensive genetic analysis. [ABSTRACT FROM AUTHOR]

Keywords: acute myeloid leukaemia; CBL syndrome; loss of heterozygosity; uniparental isodisomy; juvenile myelomonocytic leukaemia EN acute myeloid leukaemia CBL syndrome loss of heterozygosity uniparental isodisomy juvenile myelomonocytic leukaemia 665 667 3 02/02/21 20210201 NES 210201 Germline mutations in I CBL i produce a syndrome presenting in childhood or early adulthood with variable phenotype ranging from Noonan syndrome and RASopathy features, along with a strong association with the development of juvenile myelomonocytic leukaemia (JMML).1 Although somatic mutations in I CBL i have been found in approximately 5% of myeloid neoplasms,2 cancers other than JMML have not been reported frequently in CBL syndrome. Given the pattern in most patients with CBL syndrome and the heterozygous mutation status in one son, uniparental disomy is favoured as the mechanism of homozygosity in this patient. Overall, this case illustrates some of the clinical, genotypic and phenotypic characteristics of I CBL i syndrome caused by germline I CBL i variants as well as the classic LOH/UPD (uniparental disomy) frequently seen in CBL syndrome. [Extracted from the article]

Loss‐of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi‐allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi‐allelic splice site mutations, that is c.1267‐2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next‐generation sequencing. [ABSTRACT FROM AUTHOR]

De novo triplication together with uniparental disomy (UPD) is a rare genomic rearrangement, and, to our knowledge, co-occurrence has previously only been reported in two individuals. We encountered a patient with a suspected karyotype of 46,XX,del(5)(q33.1q33.3),dup(5)(q31.3q33.3) or (q33.1q35.1). Genetic analysis revealed tetrasomy of 5q33.3-q34 caused by de novo middle inverted triplication and uniparental isodisomy of 5q34-qter. Most clinical features in the patient were observed in previously reported cases of duplication overlapping with 5q33.3-q34, with the exception of hearing loss. The FOXI1 gene, which causes autosomal recessive deafness (OMIM 600791, DFNB4) when mutated, was contained within the uniparental isodisomy region (5q34-qter). However, no mutations were identified following Sanger sequencing of FOXI1. This is the first report of a patient with de novo triplication together with uniparental isodisomy of chromosome 5q. As segmental isodisomy is a post-fertilization error, it is thought to have occurred during mitosis just after fertilization via a U-type exchange, while inverted duplication could have occurred during meiosis or mitosis. This study reaffirms that the single nucleotide polymorphism (SNP) array is a powerful tool to screen for UPD in a single experiment, especially in cases of isodisomy. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Angelman and Prader-Willi syndromes are reciprocal imprinting disorders caused by loss of maternally or paternally expressed genes, respectively, within 15q11.2-q13. Angelman syndrome (AS; OMIM 105830) is a neurodevelopmental disorder and is due to the loss of maternally expressed UBE3A gene. Prader-Willi syndrome (PWS; OMIM 176270) is a clinically distinct disorder caused by the loss of paternally expressed genes in the human chromosome region 15q11.2-q13. Recently published data strongly suggest a role for the paternally expressed small nucleolar RNA (snoRNA) cluster, SNORD116, in PWS etiology. Uniparental disomy (UPD) 15 is one of the important causes of PWS and AS. Interestingly, balanced and unbalanced chromosomal aberrations in the form of Robertsonian translocation, isochromosomes, supernumerary marker chromosomes and copy number variations have been strongly linked with the occurrence of UPD. Here we report on a very unique case with a mosaic isochromosome for the entire long arm of 15, that is, i(15)(q10), resulting in mosaic uniparental isodisomy for 15q and with no copy number alterations. This is the first report of UPD15 constituted by a mosaic, but copy number neutral chromosomal rearrangement in a patient with a variant PWS-like phenotype. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Primary congenital glaucoma (PCG), a rare, severe and blinding disease, usually results from mutations in the CYP1B1 gene located in chromosome 2p22.2. Uniparental isodisomy (UPID) is also a rare condition in which a diploid offspring carries two identical copies of a single parental chromosome. By DNA sequence analysis, we found that a proband (female newborn) affected by PCG was homozygous for the null-allele F261L of the CYP1B1 gene. Her father was a heterozygous carrier for this mutation, and unexpectedly her mother carried only the G168D mutation in the heterozygous state. Segregation analysis of eight microsatellite markers which spanned the two arms of chromosome 2 was consistent with paternal isodisomy for this chromosome in the proband. To the best of our knowledge, this is the first reported case of UPID resulting in PCG and the fifth reported case of paternal UPID for chromosome 2. In addition, the absence of a clinical phenotype other than PCG confirms previous observations of there being no paternally imprinted genes in chromosome 2 that have major phenotypic effects. These results, along with previous reports, also suggest that UPID may play a relevant role in recessive diseases linked to chromosome 2. [ABSTRACT FROM AUTHOR]

Uniparental disomy (UPD) for several human chromosomes is associated with clinical abnormalities. We report the case of a 2-year-old boy with severe intrauterine and post-natal growth retardation (IUGR/PNGR) and highly variable sweat chloride concentrations. The patient was identified as heterozygous for the F508del mutation of the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Unexpectedly, the signal corresponding to the maternally inherited F508del allele appeared much more intense than the paternally derived wild allele. Molecular analysis including polymorphic marker studies, microsatellites and single-nucleotide polymorphisms subsequently showed that the boy was a carrier of a de novo mosaic maternal isodisomy of a chromosome 7 segment while there was a biparental inheritance of the rest of the chromosome. This is the first report of a mosaic partial UPD7. The matUPD7 segment at 7q21-qter extends for 72.7 Mb. The karyotype (550 bands) of our patient was normal, and fluorescence in situ hybridization with probes mapping around the CFTR gene allowed us to rule out a partial duplication. The detection of this chromosomal rearrangement confirms the hypothesis that the 7q31-qter segment is a candidate for the localization of human imprinted genes involved in the control of IUGR and PNGR. It also emphasizes the importance of searching for UPD7 in severe, isolated and unexplained IUGR and PNGR. [ABSTRACT FROM AUTHOR]

Background: Uniparental disomy (UPD) leading to autosomal recessive (AR) diseases is rare. We found an unusual homozygous state in two nonconsanguineous families, and only one parent in each family was a heterozygote. Methods: Two patients with homozygosity for pathogenic variants were revealed by whole‐exome sequencing (WES), further Sanger sequencing found that only one of the parents was a heterozygote. Initial genotype and copy number variations analysis from WES data of probands involving whole chromosomes 1 and 9 containing these two pathogenic variants were performed, genome‐wide single‐nucleotide polymorphism (SNP) array analysis was used to confirm these results. Results: Whole‐exome sequencing identified a homozygous c.3423_3424delTG mutation in AGL in patient 1 and a homozygous c.241‐1G>C mutation in SURF1 in patient 2. Further parental testing found that only the two patients' healthy fathers were heterozygous. WES‐based copy number and genotype analysis found a copy‐neutral loss of heterozygosity (LOH) of whole chromosome 1 in patient 1 and of whole chromosomes 9 and 10 in patient 2. Further genome‐wide SNP array and family haplotype analyses confirmed whole paternal uniparental isodisomy (UPiD) 1 in patient 1 and paternal UPiD 9 and maternal UPiD 10 in patient 2. Therefore, UPiD caused AR monogenic glycogen storage disease type‐III (GSDIII) in patient 1 and Leigh syndrome in patient 2 through non‐Mendelian inheritance of two mutant copies of a gene from each patient's father. Conclusion: Our report highlights that a single NGS‐based analysis could allow us to find homozygous sequence variants and copy‐neutral LOH in such cases. Our report also describes the first case of GSDIII caused by UPiD 1 and Leigh syndrome caused by UPiD 9. [ABSTRACT FROM AUTHOR]

Background: Glycogen storage disease type III (GSDIII) is caused by mutations of AGL gene with debranching enzyme deficiency. Patients with GSDIII manifest fasting hypoglycemia, hepatomegaly, hepatopathy, myopathy, and cardiomyopathy. We report on an 18‐year‐old boy with a profound growth retardation (<3 SD) besides typical clinical features of GSDIII, whereby endocrinological studies were negative. Methods and Results: Molecular analysis of AGL gene revealed the homozygous reported variant c.3903_3904insA. Since discordant results from segregation studies showed the carrier status in one parent only, SNP array and short tandem repeats analyses were performed, revealing a paternal disomy of chromosome 1 (UPD1). Conclusion: This study describes the first case of GSDIII resulting from UPD1. UPD can play an important role even in case of imprinted genes. DIRAS3 is a maternally imprinted tumor suppressor gene, located on chromosome 1p31, and implicated in growth and oncogenesis. It can be speculated that DIRAS3 overexpression might have a role in the severe short stature of our patient. The study emphasizes the importance of parental segregation analysis especially in patients with recessive conditions to look for specific genetic causes of disease and to estimate properly the risk of family recurrence. [ABSTRACT FROM AUTHOR]

Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022&#95;2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing., (© 2017 Wiley Periodicals, Inc.)