We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with ...isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM 608668) and DIP2C (OMIM 611380; UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study.
Recent evidence has implicated
in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between
and the previously known causative gene
accounting for the similarity ...in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the
gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in
on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with
variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in
appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of
being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.
We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (c.472C>T p.Arg158Cys (GenBank: NM_005718.4)). Core features in affected individuals include ...microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex, which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous ARPC4 missense variants as a cause of neurodevelopmental disorders and microcephaly.
We report a neurodevelopmental disorder with microcephaly in seven affected individuals with the same de novo variant in the ARPC4 gene. The recurrent variant in ARPC4, a subunit of the complex that catalyzes F-actin network formation, is associated with decreased F-actin in cells from affected individuals.
Several brain malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), ...cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the cortical malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain malformation associated with DEL22q11.
Potocki-Shaffer syndrome (PSS) is a rare disorder caused by haploinsufficiency of genes located on the proximal short arm of chromosome 11 (11p11.2p12). Classic features include biparietal foramina, ...multiple exostoses, profound hypotonia, dysmorphic features, and developmental delay/intellectual disability. Fewer than 40 individuals with PSS have been reported, with variable clinical presentations due in part to disparity in deletion sizes. We report on a boy who presented for initial evaluation at age 13 months because of a history of developmental delay, hypotonia, subtle dysmorphic features, and neurobehavioral abnormalities. SNP microarray analysis identified a 137 kb deletion at 11p11.2, which maps within the classically defined PSS interval. This deletion results in haploinsufficiency for all or portions of six OMIM genes: SLC35C1, CRY2, MAPK8IP1, PEX16, GYLTL1B, and PHF21A. Recently, translocations interrupting PHF21A have been associated with intellectual disability and craniofacial anomalies similar to those seen in PSS. The identification of this small deletion in a child with developmental delay and hypotonia provides further evidence for the genetic basis of developmental disability and identifies a critical region sufficient to cause hypotonia in this syndrome. Additionally, this case illustrates the utility of high resolution genomic approaches in correlating clinical phenotypes with specific genes in contiguous gene deletion syndromes.
Key Clinical Message
We report a case of an infant with congenital tufting enteropathy (CTE) who presented with severe failure to thrive despite multiple interventions. This study illustrates that ...CTE may be missed by endoscopy, and the use of chromosomal microarray and immunohistological analysis may be integral to diagnosis.
We report a case of an infant with congenital tufting enteropathy (CTE) who presented with severe failure to thrive despite multiple interventions. This study illustrates that CTE may be missed by endoscopy, and the use of chromosomal microarray and immunohistological analysis may be integral to diagnosis.
Engaging in physical activity (PA) is a key aspect in the management of axial spondyloarthritis (axial SpA), however, its relationship with clinical measures is unknown. Previous research has mainly ...focused on subjective methods of measuring PA and sedentary behaviour (SB). The aim of this study was to explore the associations between objectively measured PA and SB with clinical measures in people with established axial SpA. Fifty participants were recruited from secondary-care rheumatology outpatient services in Glasgow, UK. Clinical measures collected included; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Ankylosing Spondylitis Quality of Life (ASQOL) and the Six Minute Walk Test (6MWT). PA and SB were measured using the activPAL3 tri-axial accelerometer. Data from forty-five participants were included (23 males, average age 49 ± 12 years). Participants accumulated an average of 93.2 ± 41.5 min/day walking with an average of 7200 ± 3397 steps/day. The majority of the day (65%) was spent sitting, accumulated in prolonged bouts. Walking time and steps taken/day were associated with better BASFI (
r
= − 0.395,
p
= 0.007 and
r
= − 0.404,
p
= 0.006), ASQOL (
r
= − 0.375,
p
= 0.011 and
r
= − 0.361,
p
= 0.015) and 6MWT (
r
= 0.396,
p
= 0.007 and
r
= 0.421,
p
= 0.004); while longer walking events were associated with better BASMI (rho = − 0.352,
p
= 0.018), BASFI (rho = − 0.316,
p
= 0.034) and 6MWT (rho = 0.404,
p
= 0.006). SB was associated with worse ASQOL (
r
= 0.380,
p
= 0.010) and 6MWT (6MWT,
r
= − 0.357,
p
= 0.016). In people with axial SpA PA is associated with better function, exercise capacity and spinal mobility, while SB is associated with lower exercise capacity and poor quality of life. These findings support the promotion of PA and reduction of SB in people with axial SpA.
The purpose of this study was to assess the diagnostic yield of the traditional, comprehensive clinical evaluation and targeted genetic testing, within a general genetics clinic. These data are ...critically needed to develop clinically and economically grounded diagnostic algorithms that consider presenting phenotype, traditional genetics testing, and the emerging role of next-generation sequencing (whole-exome/genome sequencing).
We retrospectively analyzed a cohort of 500 unselected consecutive patients who received traditional genetic diagnostic evaluations at a tertiary medical center. We calculated the diagnosis rate, number of visits to diagnosis, genetic tests, and the cost of testing.
Thirty-nine patients were determined to not have a genetic disorder; 212 of the remaining 461 (46%) received a genetic diagnosis, and 72% of these were diagnosed on the first visit. The cost per subsequent successful genetic diagnosis was estimated at $25,000.
Almost half of the patients were diagnosed using the traditional approach, most at the initial visit. For those remaining undiagnosed, next-generation sequencing may be clinically and economically beneficial. Estimating a 50% success rate for next-generation sequencing in undiagnosed genetic disorders, its application after the first clinical visit could result in a higher rate of genetic diagnosis at a considerable cost savings per successful diagnosis.
Tandem mass spectrometry was adopted for newborn screening by North Carolina in April 1999. Since then, three infants with short-chain acyl-CoA dehydrogenase (SCAD) and one with isobutyryl-CoA ...dehydrogenase deficiency were detected on the basis of elevated butyrylcarnitine/isobutyrylcarnitine (C4-carnitine) concentrations in newborn blood spots analyzed by tandem mass spectrometry. For three SCAD-deficient infants, biochemical evaluation included a plasma acylcarnitine profile with markedly elevated C4-carnitine, urine organic acid analysis with markedly elevated ethylmalonic and 2-methylsuccinic acids, and markedly elevated U-13Cbutyrylcarnitine concentrations in medium from fibroblasts incubated with U-13Cpalmitic acid and excess l-carnitine, consistent with classic SCAD deficiency. Two of three infants diagnosed with classic SCAD deficiency remained asymptomatic; however, the third infant presented with seizures and a cerebral infarct at 10 wk of age. All three infants had putatively inactivating mutations in both alleles of the SCAD gene. The highly elevated plasma C4-carnitine levels in the three infants detected by newborn screening tandem mass spectrometry differentiated them from infants and children who were homozygous or compound heterozygous for one of two SCAD gene susceptibility variations; for the latter group the C4-carnitine levels were normal. Isobutyryl-CoA dehydrogenase deficiency in a fourth infant was confirmed after isolated elevation of C4-carnitine in the acylcarnitine profile.
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