American Journal of Medical Genetics Part A最新文献

Noonan syndrome (NS) is a predominantly autosomal dominant condition with various cardiac and extra-cardiac manifestations. Although it has been linked with atrial arrhythmias, ventricular arrhythmias are extremely rare in the absence of underlying structural cardiac abnormalities. We report an instance of aborted sudden cardiac arrest in a 7-year-old male with a confirmed SOS1 variant and a lack of evidence to support a structural cardiac, metabolic, or infectious etiology. This is the second reported instance of sudden cardiac arrest related to ventricular fibrillation in a child with SOS1-related NS in the absence of any structural cardiac defects. Although no definitive correlation can be ascertained from a limited existing body of knowledge surrounding SOS1 and ventricular fibrillation unrelated to structural heart defects, it provokes the idea of an arrhythmia phenotype and future research is warranted to guide proper clinical treatment, monitoring, and management of such individuals.

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is characterized by the presence of multiple small (1-2 cm in diameter) capillary malformations of the skin. This disorder has been described as two distinct entities: CM-AVM1 and CM-AVM2. The diagnosis of these disorders has been associated with pathogenic variants in the RASA1 gene for RASA1-CM-AVM, formerly known as CM-AVM1, and, more recently, the EPHB4 genes for EPHB4-CM-AVM, formerly known as CM-AVM2. Affected patients with either type may also have arteriovenous malformations and fistulas, which can cause life-threatening bleeding, congestive heart failure, or neurologic consequences such as stroke. These syndromes are typically either sporadic or inherited in an autosomal dominant manner with variable expressivity. We report a case series of a father and three daughters who have clinically diagnosed EPHB4-CM-AVM syndrome who were found to have a variant of uncertain significance (VUS) in EPHB4 that has only been reported once prior.

Radio-Tartaglia syndrome (RATARS) (MIM#619312) is a genetic disorder caused by heterozygous truncating variants of SPEN on chromosome 1p36. This syndrome is extremely rare, with only 34 cases reported to date. RATARS is characterized by developmental delay, hypotonia, and intellectual disability. In this study, we report a Japanese girl with psychomotor delay, hypotonia, and facial features resembling Down syndrome (DS). We identified a de novo heterozygous pathogenic variant of SPEN and diagnosed her with RATARS. The patient was born at 38 weeks and 1 day of gestational age, weighing 2598 g, without respiratory or feeding difficulties. We first considered DS as a differential diagnosis based on the developmental delay with hypotonia and facial features, including an upslanted palpebral fissure, hypertelorism, epicanthus folds, and a low nose; however, it was ruled out after cytogenetic testing. Microarray analysis revealed no pathogenic aberrations. We performed trio-based whole exome sequencing and identified a recurrent pathogenic variant of SPEN:NM_015001.3:c.6223_6227del, p.(Ser2075GlufsTer46). Although some features of RATARS have been reported to be similar to those of 1p36 deletion syndrome, facial similarity to DS was a characteristic of our case. Whether this feature is unique to the patient or relatively common in individuals with RATARS should be discussed further as more cases of individuals with RATARS are reported.

Conotruncal heart defects are severe congenital malformations of the outflow tract, including truncus arteriosus (TA) and double-outlet right ventricle (DORV). TA is a severe congenital heart disease (CHD) in which the main arterial outflow tract of the heart fails to separate. We recently reported TMEM260 (NM_017799.4), c.1617del (p.Trp539Cysfs*9), as a major cause of TA in the Japanese population (TMEM260 Keio-Tohoku variant) comparable to the prevalence of the 22q11.2 deletion syndrome, which accounts for 12%-35% of TA. However, no other major causes of TA have not been identified. Here, we report a family that included a TA patient and a DORV patient, harboring the compound heterozygous variants of TMEM260, a 7066-bp deletion encompassing exons 6-7 and c.1393C > T, p.(Gln465*). The allele frequency of the 7066-bp deletion was particularly high in the Japanese population (0.17%). Based on the allele frequency of this deletion and c.1617del (0.36%) in the Japanese population, TMEM260 variants might be associated with more than half of the Japanese patients with TA. This study showed that TMEM260 pathogenic variants might be the most common cause of TA in the Japanese population and could explain the wide spectrum of phenotypes associated with TMEM260-related CHD, including DORV, demonstrating the usefulness of genetic testing in Japanese patients with TA.

Biallelic variants in NRROS are associated with the rare entity of seizures, early-onset, with neurodegeneration and brain calcification (SENEBAC). Here, we report a novel loss of function variant c.720G>A, p.(Trp240*) in a patient with the clinical presentation of developmental regression, refractory seizures, and intracranial calcification. The notable clinical features included normal early development followed by regression of milestones, dysmorphism, microcephaly, refractory seizures, absent deep tendon reflexes, and hypotonia. Neuroimaging features included cerebral atrophy, thin corpus callosum, and white matter calcifications. The phenotype observed in the current report overlaps strongly with the reported phenotype in literature; however, areflexia and dysmorphic features have not been reported before with this entity. A total of 11 individuals have been reported to date. Here, we present a detailed description of the phenotype in an Indian child, expanding the clinical and molecular spectrum of NRROS-related syndrome.

Alazami syndrome is an autosomal recessive disease characterized by global developmental delay, growth restriction, and distinctive facial features. Fewer than 50 individuals are currently reported with biallelic loss of function variants in LARP7. We report the case of a 3.5-year-old boy born from nonconsanguineous parents, presenting with syndromic global developmental delay. Exome sequencing identified a homozygous frameshift pathogenic variant in LARP7. Parental analysis failed to detect the variant in the paternal sample, although the father's biological paternity was confirmed. Targeted secondary bioinformatic analyses at the LARP7 locus suggested a 45 Mb loss of heterozygosity (LOH), further confirmed by a single nucleotide polymorphism array that identified four LOH regions on chromosome 4, including one encompassing LARP7. This LOH exposes the recessive LARP7 pathogenic variant, resulting in the manifestation of Alazami syndrome. To our knowledge, this is the first reported case of Alazami syndrome due to uniparental disomy (UPD). UPD is a rare cause of autosomal recessive disorders. Its identification is crucial for genetic counseling to adjust recurrence risk for siblings. This case highlights the effectiveness and usefulness of bioinformatics algorithms applied to next generation sequencing in detecting such events.

Pathogenic variants in KIF11 are linked to microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR). To our knowledge, renal phenotypes have not been described in the literature in association with KIF11-related disorders. This study is a case report of two probands with heterozygous pathogenic variants in KIF11 who presented with the common clinical features of MCLMR but also had additional renal involvement not previously reported as associated phenotypes of MCLMR, elucidating phenotypic expansion of this syndrome.

Leber hereditary optic neuropathy (LHON) is characterized by vision loss due to the degeneration of retinal ganglion cells. LHON-Plus refers to LHON with additional extraocular findings. Neurological conditions observed in LHON-Plus include seizures, encephalopathy, movement disorders, neuropathy, and myopathy. Herein, we present a case with atypical LHON-Plus caused by a novel DNAJC30 disease-causing gene variant. A 15-year-old boy presented with acute headache, and blurred and decreased vision in both eyes. Although initial evaluation pointed toward idiopathic intracranial hypertension, the subsequent diagnostic process revealed unusual features like area postrema syndrome and T2 hyperintensity in brain magnetic resonance imaging. Consequently, antibody-negative neuromyelitis optica spectrum disorder (NMOSD) was diagnosed and treatment was commenced. Recurrent episodes of elevated intracranial pressure necessitated the insertion of a ventriculoperitoneal shunt. Exome sequencing (ES) revealed a novel homozygous variant in the DNAJC30 gene 2 years after symptom onset. Atypical LHON presentations due to nuclear gene mutations may mimic other neuroinflammatory conditions like NMOSD, necessitating thorough clinical evaluation and genetic testing. ES plays a crucial role in diagnosing complex neurological cases, enabling the identification of novel genetic variants associated with LHON and related disorders.

We aimed to describe the clinical and genetic characteristics of 16 individuals with KBG syndrome (KBGS) from 13 Indian families. We retrospectively analyzed the clinical details of individuals with KBGS harboring a likely pathogenic/pathogenic variant in ANKRD11. We also analyzed their facial gestalt using Face2Gene and recorded the top three differential disorders suggested by the application. The most frequent clinical features observed in our cohort were as follows: learning and intellectual disability-14/15 (93%), skeletal abnormalities-14/15 (93%), postnatal short stature-13/15 (87%), brachydactyly-11/15 (73%), and characteristic facial appearance-13/15 (87%). We identified 12 single nucleotide variants (SNVs), including six recurrent and six novel variants, and a copy number variant in the 16q24.3 region encompassing ANKRD11 gene. The novel variants were as follows: p.(Gln1236Ter), p.(Asp884ThrfsTer93), p.(Arg1466GlyfsTer87), p.(Tyr2056Ter), p.(Leu955TrpfsTer22), and p.(Lys766ArgfsTer10). The identified SNVs in ANKRD11 clustered around exon 9. We observed a high concordance of Face2Gene in predicting KBGS.

In this paper, we report the treatment course, magnetic resonance imaging (MRI), and electroencephalography (EEG) findings of a two-month-old girl with KCNQ2 epileptic encephalopathy caused by a de novo variant. The patient started having seizures 2 days postnatally. Despite treatment with phenobarbital, phenytoin, levetiracetam, topiramate, clonazepam, vigabatrin, clobazam, and pyridoxine, she continued to have 10 or more seizures per day. EEG recordings showed multifocal epileptiform discharges with diffuse background slowing. MRI revealed left cerebellar hypoplasia. After lacosamide administration, the severity and frequency of seizures decreased by 80%. EEG recordings showed a significant improvement. A de novo heterozygous variant of c.1681C>A (p.Pro561Thr) in the KCNQ2 gene was detected. After carbamazepine add-on treatment, the patient achieved seizure-free status for about 2 years. This case demonstrates the efficacy of lacosamide against KCNQ2 epileptic encephalopathy. To our knowledge, this is the first report to document the association between cerebellar hypoplasia and KCNQ2 variants.