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There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities., Competing Interests: Declaration of interests E.T., E.C., K.R., J. Button, A.M., M.B., J.A., A.W., M.A., T.K., A.C., S.S.A., D.L.P., and R.J.T. were employees of and stockholders in Illumina, Inc. at the time of this investigation. V.R. is a stockholder in Illumina, Inc. J.O. is a stockholder in Illumina, Inc. and employee of C2N Diagnostics. J. Belmont and T.W. are stockholders in Illumina, Inc. and were compensated as research advisors through Genetics & Genomics Services Inc. C.S. was compensated as a consultant through Genetics & Genomics Services Inc. for statistical analysis. K.M. is an employee of Ambry Genetics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants., Methods: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model., Results: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2 301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model., Conclusion: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity., Competing Interests: Conflict of Interest Amber Begtrup, Hong Cui, and Aida Telegrafi are employees of GeneDx, LLC. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive condition having significant clinical overlap with trisomy 18. Though rare in the general population, it is quite common in the Hutterites of the United States and Canada. The carrier frequency in the Hutterite population is estimated to be one in 10, making BCS one of the most commonly inherited genetic diseases in any human group studied to date. We describe two infant patients who were initially thought to have trisomy 18, but for whom chromosome studies were normal. Additionally, we briefly review the historical background of the Anabaptist Hutterite populations in South Dakota, compare the clinical findings in BCS and trisomy 18 and discuss the importance of genetic counseling for couples of Hutterite descent.

We report on a 20-month-old male, diagnosed prenatally with de novo mosaic ring chromosome 18 and low level monosomy 18, who also exhibited an inherited and apparently balanced translocation between chromosomes 3 and 6. We believe this to be the first reported case of prenatally diagnosed mosaic ring chromosome 18 and monosomy 18 in which the child was carried to term. Ring chromosomes are associated with an abnormal phenotype that is dependent on the amount of material that is deleted from the p and q arms. This child has a 22.5 Mb deletion of 18q and a 2.8 Mb deletion of 18p as a result of ring formation. Although the large deletion has resulted in some developmental delays and health problems, the child is making more developmental progress than was anticipated prenatally. We present his clinical course and the genetic counseling challenges associated with this case.

Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenase-deficient patients through newborn screening due to an elevation of C4-acylcarnitine in dried blood spots. Because C4-acylcarnitine represents both isobutyryl- and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C4-acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions., Methods: Fibroblast cultures were established from infants with C4-acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydrogenase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase- and short-chain acyl-CoA dehydrogenase-deficient patients., Results: Quantification of C4-acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation of isobutyryl-CoA dehydrogenase-deficient from short-chain acyl-CoA dehydrogenase-deficient cases. In nine unrelated patients with isobutyryl-CoA dehydrogenase deficiency, 10 missense mutations were identified in ACAD8. To date, 10 of the 13 isobutyryl-CoA dehydrogenase-deficient patients remain asymptomatic, two were lost to follow-up, and one patient required frequent hospitalizations due to emesis and dehydration but is developing normally at 5 years of age., Conclusion: Although the natural history of isobutyryl-CoA dehydrogenase deficiency must be further defined, we have developed an algorithm for rapid laboratory evaluation of neonates with an isolated elevation of C4-acylcarnitine identified through newborn screening.

The isobutyryl-CoA dehydrogenase (IBD) enzyme is involved in the degradation of valine. IBD deficiency was first reported in 1998 and subsequent genetic investigations identified acyl-CoA dehydrogenase (ACAD) 8, now IBD, as the gene responsible for IBD deficiency. Only three individuals homozygous or compound heterozygous for variations in the IBD gene have been reported. We present IBD deficiency in an additional four newborns with elevated C(4)-carnitine identified by tandem mass spectrometry (MS/MS) screening in Denmark and the United States. Three showed urinary excretions of isobutyryl-glycine, and in vitro probe analysis of fibroblasts from two newborns indicated enzymatic IBD defect. Molecular genetic analysis revealed seven new rare variations in the IBD gene (c.348C>A, c.400G>T, c.409G>A, c.455T>C, c.958G>A, c.1000C>T and c.1154G>A). Furthermore, sequence analysis of the short-chain acyl-CoA dehydrogenase (SCAD) gene revealed heterozygosity for the prevalent c.625G>A susceptibility variation in all newborns and in the first reported IBD patient. Functional studies in isolated mitochondria demonstrated that the IBD variations present in the Danish newborn (c.409G>A and c.958G>A) together with a previously published IBD variation (c.905G>A) disturbed protein folding and reduced the levels of correctly folded IBD tetramers. Accordingly, low/no IBD residual enzyme activity was detectable when the variant IBD proteins were overexpressed in Chang cells.

The Marshall-Smith syndrome (MSS) is a distinct malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia. At least 33 cases have been reported in the literature, mostly as single case reports or small series. The purpose of the present study is to report on the clinical findings and natural history of MSS in five children and to review the features of three others previously reported, with particular attention to the skeletal and connective tissue findings. Our study demonstrates an increased rate of nontraumatic fractures and other bony and connective tissue abnormalities that support the hypothesis that MSS should be considered an osteochondrodysplasia. In addition, long-term survival beyond infancy is possible if respiratory problems are expectantly and aggressively managed., ((c) 2005 Wiley-Liss, Inc.)

Inborn errors of fatty acid oxidation, including medium chain acyl CoA dehydrogenase (MCAD) deficiency are readily detectable and treatable metabolic disorders in which recognition of symptoms is important. Symptoms occur when there is fasting, often associated with illness. If not diagnosed, these inborn errors of metabolism can result in sudden death classified as SIDS. These disorders can be diagnosed by ordering plasma or blood spot acylcarnitine profiles.

A trisomy 17pter --> p11.2 derived from a supernumerary de novo satellited marker was identified by GTG bands and fluorescent in situ hybridisation (FISH) in amniocytes of a fetus with malformations and intrauterine growth retardation (IUGR). At 39 weeks a male infant with a phenotype similar to other postnatal cases of 'pure' complete trisomy 17p was born. Some additional clinical features, however, make him more severely affected than previous patients.

We describe a "new" syndrome of spondylospinal thoracic dysostosis with a short curved spine and fusion of the spinous processes, short thorax with "crab-like" configuration of the ribs, pulmonary hypoplasia, severe arthrogryposis and multiple pterygia, and hypoplastic maxilla and mandible in two siblings. This appears to be an autosomal recessive lethal trait. A literature review revealed two reports of four similar or related cases.

X-linked hereditary spastic paraplegias (HSP) present with two distinct phenotypes, pure and complicated. The pure form is characterized by spasticity and gait difficulties but lacks the additional features (nystagmus, dysarthria, mental retardation) present in the complicated form. The complicated form is heterogeneous, caused by mutations of the L1CAM gene at Xq28 (SPG1) or the PLP gene at Xq22 (SPG2) that is allelic to Pelizaeus-Merzbacher disease (PMD). Since in one kindred (K313) the pure form of HSP was also mapped to Xq22, this raises the issue as to whether a pure form of HSP exists that is allelic to X-linked complicated HSP (SPG2) and PMD. To answer this question, we carried out linkage analysis in a new pedigree with pure HSP (K101) and refined linkage in pedigree K313. The PLP gene was also screened for mutation by direct sequencing and reverse-transcriptase polymerase chain reaction (RT-PCR). In both families, the disease locus mapped to Xq22 with Lod scores at zero recombination of 5.3 for COL4A5 2B6 in K313 and 2.4 for DXS101 in K101. A T to C transition in exon 5 of the PLP gene was identified from affected individuals of K313. This transition causes a Ser to Pro mutation in the major extracellular loop of PLP/DM20. This finding demonstrates that a form of X-linked pure spastic paraplegia, X-linked complicated HSP (SPG2) and PMD are allelic disorders. There was no evidence of mutations in either coding sequences or the intron/exon junctions of PLP in pedigree K101, suggesting that the disease-producing mutation may be in the noncoding portions of PLP or in a nearby gene.

Wolf-Hirschhorn syndrome (WHS) is due to a deletion in the terminal band of 4p16.3. Among loci that have been involved in deletions are D4S98, D4S95, D4S125, D4F26, as shown by PCR typing, Southern blot hybridization, and/or fluorescent in situ hybridization (FISH). Currently, FISH detection of WHS is predicted upon the deletion of the D4F26 locus with failure to hybridize to pC847.351, a commercially available cosmid probe. A WHS patient is shown to have an interstitial deletion, by hemizygosity at D4S98 and D4S95 but not at D4F26. This suggests that the tip of 4p, specifically D4F26, is not a critical deletion site for WHS.

We report on a 3-generation family with an interstitial deletion of the short arm of chromosome 5. Varied manifestations were found among the affected individuals including microcephaly, hypertonia, and micrognathia; mental retardation was common to all affected individuals. High resolution chromosome analysis was interpreted as del(5) (pter- > p14.3::p13.3- > qter). Molecular comparison of the deletion in this family with individuals with other 5p deletions suggests that the clinical findings are due specifically to the chromosomal material deleted from 5p13.

Roberts-SC phocomelia syndrome (RS) is an autosomal recessive disorder of symmetric limb defects, craniofacial abnormalities, pre- and postnatal growth retardation, and mental retardation. Patients with RS have been reported to have premature separation of heterochromatin of many chromosomes and abnormalities in the cell-division cycle. We report an infant whose clinical and radiologic findings resemble those of RS but who lacks the cytogenetic and cell division abnormalities reported in RS. This patient may represent a variant of RS or a new syndrome.

Five of 13 patients with microphthalmia or clinical anophthalmia studied in an institution of 650 mentally retarded adults had hypogonadotropic hypogonadism. Four males had low testosterone levels and sexual infantilism, manifesting as micropenis with small testes or cryptorchidism. One female had primary amenorrhea. All 5 patients had low gonadotropin levels, confirming a hypothalamic or pituitary basis for their hypogonadism. Thyroxin, thyroid stimulating hormone, prolactin, and A.M. cortisol were also measured and were normal. All patients with hypogonadotropic hypogonadism were chromosomally normal and had variable central nervous system defects, suggesting that they comprise a heterogeneous group of disorders. Microphthalmia or anophthalmia in a mentally retarded patient is associated with hypogonadotropic hypogonadism.

Because alcohol has an adverse effect on zinc homeostasis, this study was designed to study if zinc content of the diet modifies the severity of fetal alcohol syndrome in a mouse model. The effect of varying zinc intake on the progeny of pregnant mice fed a liquid diet containing 15% of the calories as ethanol was studied. Prenatal mortality was higher when the mothers consumed alcohol with inadequate zinc intake. Because of the adverse effect of alcohol on zinc homeostasis and because zinc deficiency has been shown to potentiate alcohol embryopathy, one group was given zinc supplementation to four times the Recommended Dietary Allowance. Supplemental zinc above the Recommended Dietary Allowance was not protective and appeared to have an adverse effect on fetal weight and prenatal mortality. These results suggest that zinc intake should be optimized during pregnancy but that zinc supplementation above the Recommended Dietary Allowance does not reduce the incidence or severity of fetal alcohol syndrome.

The Aarskog (facial-digital-genital) syndrome is an X-linked disorder in which short stature is accompanied by hypertelorism, digital anomalies, and shawl scrotum. Except for hypertelorism and blepharoptosis, ophthalmic abnormalities have been rarely noted in this condition. We examined four patients who had Aarskog syndrome and unilaterally or bilaterally decreased vision on initial examination. Three family members had V-pattern esotropia, latent nystagmus, inferior oblique overaction, and amblyopia. A fourth patient had bilateral blepharoptosis and severe astigmatism. Other ocular features included hyperopia, anisometropia, deficient ocular elevation, blue sclerae, and posterior embryotoxon. These findings underscore the need for ophthalmic examination in asymptomatic patients with Aarskog syndrome to rule out treatable causes of visual loss.

A patient with Silver-Russell Syndrome with previously undescribed absence of two fingers plus syndactyly of the opposite hand is reported.

We describe a large family (K313) having 12 males affected with X chromosome-linked recessive hereditary spastic paraplegia (HSP). The disease phenotype in K313 is characterized by hyperreflexia and a spastic gait, but intelligence is normal. Carrier females have normal gait and unremarkable neurologic profiles. Eight widely spaced X-linked DNA markers were used to genotype 43 family members. In contrast to a published study of another family, in whom complete linkage of X-linked recessive HSP to distal chromosome Xq markers DXS15 and DXS52 was reported, we observed complete linkage with two DNA markers, pYNH3 and DXS17, located on the middle of the long arm of the X chromosome. These data have been combined with linkage data from a large reference panel of normal families to localize the new X-chromosome marker, pYNH3, and to provide evidence of significant locus heterogeneity between phenotypically distinct forms of X-linked recessive HSP.

Fragile X syndrome is the second most common chromosomal cause of mental retardation (MR). The calculated incidence is 1/1000, making accurate and early diagnosis important for specific preventive, pharmacologic, and cognitive treatment. The timely diagnosis in males is facilitated by the characteristic phenotype and an association with autism. In contrast, in females heterozygous for fragile X, the characteristic phenotype and infantile autism are rarely reported. We present two females with cytogenetic expression of the fragile X chromosome for whom the studies were performed because of the presence of autism or prominent autistic features and a behavioral and physical phenotype consistent with fragile X syndrome. The first female, age three years, has autism, hyperactivity, echolalia, language delay, hand stereotypies, and mild MR. The characteristic phenotype was not present nor was there a family history of X-linked MR. Fragile X expression was 6% in the proband, 3% in the mother and 1% (normal) in the father. The second child, seven years old, has prominent autistic features, hyperactivity, mild MR, mild language disorder, and a family history consistent with X-linked MR. Fragile X expression was 3% in the proband and 0% in the mother. These cases support the occurrence of fragile X in autistic females and emphasize the importance of cytogenetic screening for fragile X in this high risk population. Early diagnosis of fragile X allows precise genetic counseling and more specific cognitive and pharmacologic treatment.

The myotubular myopathies are a heterogeneous group of muscle disorders in which x-linked, autosomal recessive, and autosomal dominant inheritance have been reported. Female carriers of x-linked myotubular myopathy have been reported to have abnormal muscle biopsies. We report a woman who had a normal muscle biopsy but who had 2 sons with myotubular myopathy by different fathers, indicating that a normal muscle biopsy of the mother cannot exclude x-linked inheritance. The quantity of fetal activity correlated with the severity of the disorder in this pedigree.

Because alcoholism has adverse effects on zinc nutrition and many pregnant women consume less than the recommended dietary allowances of zinc, we postulated that zinc deficiency acts as a co-teratogen with alcohol in the fetal alcohol syndrome. We compared the effects of alcohol on progeny of pregnant mice fed a zinc-deficient diet compared to those fed a diet with adequate zinc. Pregnant CBA mice (n = 66) were fed the Lieber-DeCarli liquid diet with 0, 15, or 20% ethanol-derived calories containing 0.3 (low) or 8.5 (high) micrograms zinc/ml. Dams were sacrificed on day 18 of gestation. Resorptions, malformations, and individual fetal weights were recorded. Analysis of fetuses included assays for zinc, assessment of soft tissue malformations, and alizarin red staining for skeletal malformations. Fetal weights were lower in the groups fed the zinc-deficient diet for each concentration of alcohol (p less than 0.005). The groups fed the combination of low zinc plus alcohol had 37-52% resorptions, while the animals on the zinc-deficient diet without alcohol or the high zinc diet with alcohol had 0-2% resorptions. Skeletal malformations were related to alcohol concentration but not zinc intake, while external malformations were higher in those maintained on the low zinc-ethanol diet. These results suggest that zinc deficiency potentiated the teratogenic effects of alcohol and that nutritional intervention for alcoholic women during pregnancy might reduce the incidence or severity of fetal alcohol syndrome.