Dataset Information

Expanding the clinical and mutational spectrum of germline ABL1 mutations-associated syndrome: A case report.

ABSTRACT:

Rationale

Clinical and genetic management of patients with rare syndromes is often a difficult, confusing, and slow task.

Patient concerns

Male child patient with a multisystemic disease showing congenital heart defects, facial dysmorphism, skeletal malformations, and eye anomalies.

Diagnosis

The patient remained clinically undiagnosed until the genetic results were conclusive and allowed to associate its clinical features with the germline ABL1 mutations-associated syndrome.

Interventions

We performed whole-exome sequencing to uncover the underlying genetic defect in this patient. Subsequently, family segregation of identified mutations was performed by Sanger sequencing in all available family members.

Outcomes

The only detected variant compatible with the disease was a novel heterozygous nonframeshift de novo deletion in ABL1 (c.434_436del; p.Ser145del). The affected residue lays in a functional domain of the protein, it is highly conserved among distinct species, and its loss is predicted as pathogenic by in silico studies.

Lessons

Our results reinforce the involvement of ABL1 in clinically undiagnosed cases with developmental defects and expand the clinical and genetic spectrum of the recently reported ABL1-associated syndrome. In this sense, we described the third germline ABL1 causative mutation and linked, for the first time, ocular anterior chamber anomalies to this pathology. Thus, we suggest that this disorder may be more heterogeneous than is currently believed and may be overlapping with other multisystemic diseases, hence genetic and clinical reassessment of this type of cases should be considered to ensure proper diagnosis.

SUBMITTER: Bravo-Gil N

PROVIDER: S-EPMC6417628 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Expanding the clinical and mutational spectrum of germline ABL1 mutations-associated syndrome: A case report.

Bravo-Gil Nereida N Marcos Irene I González-Meneses Antonio A Antiñolo Guillermo G Borrego Salud S

Medicine 20190301 10

<h4>Rationale</h4>Clinical and genetic management of patients with rare syndromes is often a difficult, confusing, and slow task.<h4>Patient concerns</h4>Male child patient with a multisystemic disease showing congenital heart defects, facial dysmorphism, skeletal malformations, and eye anomalies.<h4>Diagnosis</h4>The patient remained clinically undiagnosed until the genetic results were conclusive and allowed to associate its clinical features with the germline ABL1 mutations-associated syndrom ...[more]

PMID: 30855488

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Project description:BackgroundCommon clinical findings in patients with 19p13.3 duplication include intrauterine growth restriction, intellectual disability, developmental delay, microcephaly, and distinctive facial features. In this study, we report the case of a patient with 19p13.3 microduplication and novel clinical findings, specifically nephrotic syndrome.Case presentationsA 4-year-old girl was admitted to our hospital in December 2020 with a fever and cough that had persisted for 3 days. A series of treatments, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) were performed. Relevant literature was reviewed using the search terms "19p13.3" and "19p13.3 microduplication syndrome" in the China Knowledge Network, Wanfang Database, Weipu Journal Service Platform, and PubMed (date range: database establishment to September 2023). In addition to common symptoms, such as developmental delay, microcephaly, distinctive facial features, and congenital heart defects, the patient also had nephrotic syndrome, a previously unreported phenomenon. CMA results showed a 3.6 Mb fragment duplication (copy number: 3) in the chr19p13.3 region, containing 127 protein-coding genes (including CELF5, NFIC, SMIM24, PIAS4, ATCAY, MAP2K2, and ZBTB7A). WES revealed a filamin C mutation (p.Glu309Valfs × 11). The mutation status of the patient and her father was heterozygous, whereas the mutation was not detected in the mother.ConclusionMicroduplication in the 19p13.3 region could be one of the genetic factors contributing to the observed clinical phenotypes. However, patients with developmental delay, microcephaly, distinctive facial features, congenital heart defects, and urogenital system disorders may exhibit these manifestations due to various genetic syndromes; therefore, simply considering the possibility of 19p13.3 microduplication syndrome based on these non-specific features is not sufficient. Further comprehensive evaluations, including CMA, should be conducted in conjunction with other genetic tests and detailed clinical examinations to accurately determine the underlying genetic causes.

Project description:BACKGROUND:Congenital hypogonadotropic hypogonadism (CHH) is a rare disease, triggered by defective GnRH secretion, that is usually diagnosed in late adolescence or early adulthood due to the lack of spontaneous pubertal development. To date more than 30 genes have been associated with CHH pathogenesis with X-linked recessive, autosomal dominant, autosomal recessive and oligogenic modes of inheritance. Defective sense of smell is present in about 50-60% of CHH patients and called Kallmann syndrome (KS), in contrast to patients with normal sense of smell referred to as normosmic CHH. ANOS1 and FGFR1 genes are all well established in the pathogenesis of CHH and have been extensively studied in many reported cohorts. Due to rarity and heterogenicity of the condition the mutational spectrum, even in classical CHH genes, have yet to be fully characterized. METHODS:To address this issue we screened for ANOS1 and FGFR1 variants in a cohort of 47 unrelated CHH subjects using targeted panel sequencing. All potentially pathogenic variants have been validated with Sanger sequencing. RESULTS:Sequencing revealed two ANOS1 and four FGFR1 mutations in six subjects, of which five are novel and one had been previously reported in CHH. Novel variants include a single base pair deletion c.313delT in exon 3 of ANOS1, three missense variants of FGFR1 predicted to result in the single amino acid substitutions c.331C > T (p.R111C), c.1964 T > C (p.L655P) and c.2167G > A (p.E723K) and a 15 bp deletion c.374_388delTGCCCGCAGACTCCG in exon 4 of FGFR1. Based on ACMG-AMP criteria reported variants were assigned to class 5, pathogenic or class 4, likely pathogenic. Protein structural predictions, the rarity of novel variants and amino acid conservation in case of missense substitutions all provide strong evidence that these mutations are highly likely to be deleterious. CONCLUSIONS:Despite the fact that ANOS1 and FGFR1 are classical CHH genes and were thoroughly explored in several CHH cohorts we identified new, yet undescribed variants within their sequence. Our results support the genetic complexity of the disorder. The knowledge of the full genetic spectrum of CHH is increasingly important in order to be able to deliver the best personalised medical care to our patients.

Dataset Information

Expanding the clinical and mutational spectrum of germline ABL1 mutations-associated syndrome: A case report.

Rationale

Patient concerns

Diagnosis

Interventions

Outcomes

Lessons

Publications

Expanding the clinical and mutational spectrum of germline ABL1 mutations-associated syndrome: A case report.

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