Expanding the phenotypic spectrum of Dejerine-Sottas syndrome caused by the trembler mutation.

Dejerine-Sottas syndrome (DSS) is the earlier onset, more severe form of Charcot-Marie-Tooth (CMT) disease with heterogenous neurologic manifestations in addition to the peripheral neuropathy depending not only on the underlying causative gene but also the specific mutation. The Trembler mutation is an uncommon missense mutation in the PMP22 gene, the most commonly mutated gene responsible for CMT. We report two cases of DSS in a mother and son with the Trembler mutation, with associated findings of hearing loss and cognitive impairment. The mother had developmental gait abnormalities and became wheelchair bound in adolescence. She displayed impairment on cognitive and audiologic testing. Her son had similar developmental gait abnormalities and became wheelchair bound at age 19. Cognitive function showed an earlier decline in the son as compared to his mother. This report extends the clinical spectrum of the Trembler mutation in humans to include associated hearing loss with cognitive impairment.

Whole genome sequencing identifies variants associated with sarcoidosis in a family with a high prevalence of sarcoidosis.

OBJECTIVE: We studied genetic risk factors associated with sarcoidosis within a family with a high prevalence of this disease. METHODS: We studied 41 members of a family with a high rate of sarcoidosis, including an index patient with treatment-resistant neurosarcoidosis. Whole genome sequencing was performed for six affected family members and variations associated with loss of function were filtered out as candidate genes. Findings were validated by using amplicon sequencing within all 41 family members with DNA available and candidate genes were screened on absence and presence within the sarcoidosis affected and non-affected. RESULTS: Family members (n = 61) from 5 generations were available for participation including 13 subjects diagnosed with sarcoidosis (20%). Analyses identified 36 candidate variants within 34 candidate genes. Variations within three of these genes (JAK2, BACH2, and NCF1) previously have been associated with autoimmune diseases. CONCLUSIONS: We identified 34 genes with a possible role in the etiology of sarcoidosis, including JAK2. Our results may suggest evaluation of JAK inhibitors in treatment-resistant sarcoidosis. Key Points • JAK2 has a potential role in the etiology of sarcoidosis and is a potential therapeutic target. • We identified 33 additional candidate genes of which BACH2 and NCF1 have been previously associated with autoimmune disease.

IKZF1 Deletion Subtyping and Outcome Analysis in BCR-ABL1-Negative Pediatric B-Cell Acute Lymphoblastic Leukemia: A Single-Institution Experience from North India.

BACKGROUND: IKZF1 deletions are associated with adverse outcomes in B-cell acute lymphoblastic leukemia (B-ALL). We assessed the prevalence and clinical impact of functional subtypes of IKZF1 deletions in pediatric BCR-ABL1-negative B-ALL. PATIENTS AND METHODS: This retrospective study of IKZF1 deletions was done in cases of pediatric BCR-ABL1-negative B-ALL. The genomic DNA of cases, over a 53-month period, was analyzed using multiplex ligation-dependent probe amplification and multiplex fluorescent polymerase chain reaction. The deletions were divided into functional subgroups: (1) loss-of-function/haploinsufficiency, (2) dominant-negative, and (3) a combination of both types of deletion. The post-induction remission status, event-free survival (EFS), and overall survival (OS) were noted. RESULTS: Out of 320 cases, 47 (14.7%) had IKZF1 deletions. Thirty-six of the 47 (77%) had loss-of-function deletions, 10 (21%) had dominant-negative deletions, and one (2%) had a combination of both types. The post-induction remission rates in cases with loss-of-function deletions (22/30, 73%; P = .060) and dominant-negative deletions (4/5, 80%; P = .517) were lower compared with those without deletions (215/248, 86.7%). These cases also had worse median EFS: 21.1 months (P = .006) for loss-of-function and 15.4 months (P = .156) for dominant-negative deletions, compared with 46.4 months in cases without IKZF1 deletions. They also had worse median OS: 23.4 months (P = .012) for loss-of-function deletions and 15.7 months (P = .233) for dominant-negative deletions, compared with median not reached in cases without IKZF1 deletions. CONCLUSION: The IKZF1 deletions were seen in 14.7% of BCR-ABL1-negative pediatric B-ALL. Most of these deletions (77%) were loss-of-function type. The cases with loss-of-function deletions had lower remission rates and poor EFS and OS compared with cases without IKZF1 deletions. A similar trend of poor outcome was seen in the few cases with dominant-negative IKZF1 deletions.

A case report of hypersomnia in tetrasomy X improved with medical therapy.

Tetrasomy X is a rare chromosomal anomaly in which sleep disorders have not been previously reported. We report on one patient with tetrasomy X and hypersomnia successfully treated with psychostimulant therapy. Sleep disorders are rarely reported in chromosomal anomalies. Clinicians should screen patients for sleep disorders and manage them appropriately.

Molecular genetic profile in BCR-ABL1 negative pediatric B-cell acute lymphoblastic leukemia can further refine outcome prediction in addition to that by end-induction minimal residual disease detection.

The recently proposed molecular genetic criteria promise improved risk-prediction in B-cell acute lymphoblastic leukemia (B-ALL). This study assesses their utility in BCR-ABL1 negative pediatric B-ALL, particularly with respect to end-induction minimal residual disease (MRD). The DNA was analyzed for copy number alterations in CDKN2A/B, PAX5, IKZF1, and other genes. Seventy-six cases with median age 7 years (2 months-18 years) included MRD-positive (24; 32%), and MRD negative-standard (20; 26%), intermediate (20; 26%), & high risk (12;16%) cases. The risk classification was based on age, initial total leukocyte count, central nervous system involvement, cytogenetics, day 8 prednisolone response and MRD status after induction chemotherapy. The genetic profile based on Moorman's criteria identified two subgroups with different event free survival (EFS) (0.77 vs. 0.38; p = .045) and overall survival (OS) (0.90 vs. 0.30; p = .037) in the MRD-negative intermediate-risk group. The genetic profile also separated two subgroups with different EFS (0.75 vs. 0.41; p = .036) in the MRD-positive group, however the OS was not different (0.75 vs. 0.57; p = .293).

Gene copy number alteration profile and its clinical correlation in B-cell acute lymphoblastic leukemia.

The genes related to B-cell development are frequently altered in B-cell acute lymphoblastic leukemia (B-ALL). One hundred sixty-two newly diagnosed B-ALL cases, median age 8.5 years (2 months-67 years), were prospectively analyzed for copy number alterations (CNAs) in CDKN2A/B, IKZF1, PAX5, RB1, ETV6, BTG1, EBF1, and pseudoautosomal region genes (CRLF2, CSF2RA, IL3RA) using multiplex ligation-dependent probe amplification. The CNAs were detected in 114 (70.4%) cases; most commonly affected genes being CDKN2A/B-55 (34%), PAX5-51 (31.5%), and IKZF1-43 (26.5%). IKZF1 and RB1 deletions correlated with higher induction failure. Patients classified as good-risk, according to the integrated CNA profile and cytogenetic criteria, had lower induction failure [5 (8.6%) vs. 20 (25.3%); p = 0.012]. Those classified as good-risk, based on CNA profile irrespective of cytogenetics, also showed lower induction failure [6 (9.4%) vs. 19 (26%); p = 0.012]. The CNA profile identified patients with better induction outcome and has a potential role in better risk stratification of B-ALL.