Whole-genome sequencing reveals a novel pathogenic GRIN2B variant in a patient with neurodevelopmental disorder and an inv(6)(p24p11.2)pat.

INTRODUCTION: Neurodevelopmental disorders (NDDs) are diverse and can be explained by either genomic aberrations or single nucleotide variants (SNVs). Most likely due to methodological approaches and/or disadvantages, the concurrence of both genetic events in a single patient has hardly been reported and even more rarely the pathogenic variant has been regarded as the cause of the phenotype when a chromosomal alteration is initially identified. CASE PRESENTATION: Here, we describe a NDD patient with a 6p non-pathogenic paracentric inversion paternally transmitted and a de novo pathogenic variant in the GRIN2B gene. Molecular-cytogenetic studies characterized the familial 6p inversion and revealed a paternal 9q inversion not transmitted to the patient. Subsequent whole-genome sequencing (WGS) in the patient-father dyad corroborated the previous findings, discarded inversions-related cryptic genomic rearrangements as causative of the patient's phenotype, and unveiled a novel heterozygous GRIN2B variant (p.(Ser570Pro)) only in the proband. In addition, Sanger sequencing ruled out such a variant in her mother and thereby confirmed its de novo origin. Due to predicted disturbances in the local secondary structure, this variant may alter the ion channel function of the M1 transmembrane domain. Other pathogenic variants in GRIN2B have been related to the autosomal dominant neurodevelopmental disorder MRD6 (Intellectual developmental disorder, autosomal dominant 6, with or without seizures), which presents with a high variability ranging from mild intellectual disability (ID) without seizures to a more severe encephalopathy. In comparison, our patient's clinical manifestations include, among others, mild ID and brain anomalies previously documented in subjects with MRD6. CONCLUSION: Occasionally, gross chromosomal abnormalities can be coincidental findings rather than a prime cause of a clinical phenotype (even though they appear to be the causal agent). In brief, this case underscores the importance of comprehensive genomic analysis in unraveling the wide-ranging genetic causes of NDDs and may bring new insights into the MRD6 variability.

A chromoanagenesis-driven ultra-complex t(5;7;21)dn truncates neurodevelopmental genes in a disabled boy as revealed by whole-genome sequencing.

Germline or constitutional chromoanagenesis-related complex chromosomal rearrangements (CCRs) are rare, apparently "all-at-once", catastrophic events that occur in a single cell cycle, exhibit an unexpected complexity, and sometimes correlate with a severe abnormal phenotype. The term chromoanagenesis encompasses three distinct phenomena, namely chromothripsis, chromoanasynthesis, and chromoplexy. Herein, we found hallmarks of chromothripsis and chromoplexy in an ultra-complex t(5;7;21)dn involving several disordered breakpoint junctions (BPJs) accompanied by some microdeletions and the disruption of neurodevelopmental genes in a patient with a phenotype resembling autosomal dominant MRD44 (OMIM 617061). G-banded chromosomes and FISH showed that the CCR implied the translocation of the 5p15.2→pter segment onto 7q11.23; in turn, the fragment 7q11.23→qter of der(7) separated into two pieces: the segment q11.23→q32 translocated onto 5p15.2 and fused to 21q22.1→ter in the der(5) while the distal 7q32→qter segment translocated onto der(21) at q22.1. Subsequent whole-genome sequencing unveiled that CCT5, CMBL, RETREG1, MYO10, and TRIO from der(5), IMMP2L, TES, VPS37D, DUS4L, TYW1B, and FEZF1-AS1 from der(7), and TIAM1 and SOD1 from der(21), were disrupted by BPJs, whereas some other genes (predicted to be haplosufficient or inconsequential) were completely deleted. Although remarkably CCT5, TRIO, TES, MYO10, and TIAM1 (and even VPS37D) cooperate in key biological processes for normal neuronal development such as cell adhesion, migration, growth, and/or cytoskeleton formation, the disruption of TRIO most likely caused the patient's MRD44-like phenotype, including intellectual disability, microcephaly, finger anomalies, and facial dysmorphia. Our observation represents the first truncation of TRIO related to a chromoanagenesis event and therefore expands the mutational spectrum of this crucial gene. Moreover, our findings indicate that more than one mechanism is involved in modeling the architecture of ultra-complex rearrangements.

Generalized hypertrichosis syndromes in Mexico.

Hypertrichosis is a rare condition characterized by excessive hair in areas of the body that are not predominantly androgen dependent. We can identify three main syndromes with congenital generalized hypertrichosis terminalis described in Mexico. The first is X-linked generalized hypertrichosis, an ultra-rare disease, with few cases reported to date. The second is Cantú syndrome, also known as hypertrichotic osteochondrodysplasia, which has a wide spectrum of clinical manifestations and is caused by pathogenic variants in ABCC9 and KCNJ8. The third is congenital hypertrichosis terminalis with or without gingival hyperplasia, which displays other features and involves several associated genes. The first two syndromes were described by the Mexican geneticist José María Cantú, and the concept of atavistic genes was invoked to explain the emergence of this outstanding trait. By understanding the genetic and pathophysiological basis of hypertrichosis, we can offer effective treatment to patients and help solve esthetic problems related to hair growth.

Williams-Beuren syndrome in Mexican patients confirmed by FISH and assessed by aCGH.

Williams-Beuren syndrome (WBS) has a prevalence of 1/7500-20000 live births and results principally from a de novo deletion in 7q11.23 with a length of 1.5 Mb or 1.8 Mb. This study aimed to determine the frequency of 7q11.23 deletion, size of the segment lost, and involved genes in 47 patients with a clinical diagnosis of WBS and analysed by fluorescence in situ hybridization (FISH); among them, 31 had the expected deletion. Micro-array comparative genomic hybridization (aCGH) confirmed the loss in all 18 positive-patients tested: 14 patients had a 1.5 Mb deletion with the same breakpoints at 7q11.23 (hg19: 72726578-74139390) and comprising 24 coding genes from TRIM50 to GTF2I. Four patients showed an atypical deletion: two had a 1.6 Mb loss encompassing 27 coding genes, from NSUN5 to GTF2IRD2; another had a 1.7 Mb deletion involving 27 coding genes, from POM121 to GTF2I; the remaining patient presented a deletion of 1.2 Mb that included 21 coding genes from POM121 to LIMK1. aCGH confirmed the lack of deletion in 5/16 negative-patients by FISH. All 47 patients had the characteristic facial phenotype of WBS and 45 of 47 had the typical behavioural and developmental abnormalities. Our observations further confirm that patients with a classical deletion present a typical WBS phenotype, whereas those with a high (criteria of the American Association of Pediatrics, APP) clinical score but lacking the expected deletion may harbour an ELN point mutation. Overall, the concomitant CNVs appeared to be incidental findings.

22q11.2 deletion detected by in situ hybridization in Mexican patients with velocardiofacial syndrome-like features.

INTRODUCTION: Deletion 22q11.2 occurs in 1:4,000-1:6,000 live births while 10p13p14 deletion is found in 1:200,000 newborns. Both deletions have similar clinical features such as congenital heart disease and immunological anomalies. OBJECTIVE: We looked for a 22q11.2 deletion in Mexican patients with craniofacial dysmorphisms suggestive of DiGeorge or velocardiofacial syndromes and at least one major phenotypic feature (cardiac anomaly, immune deficiency, palatal defects or development delay). METHODS: A prospective study of 39 patients recruited in 2012-2015 at the Instituto Mexicano del Seguro Social at Guadalajara, Mexico. The patients with velocardiofacial syndrome-like features or a confirmed tetralogy of Fallot (TOF) or complex cardiopathy were studied by G-banding and fluorescence in situ hybridization (FISH) with a dual TUPLE1(HIRA)/ARSA or TUPLE1(22q11)/22q13(SHANK3) probe, six patients without the 22q11.2 deletion (arbitrarily selected) were tested with the dual DiGeorge II (10p14)/D10Z1 probe. RESULTS: Twenty-two patients (7 males and 15 females) had the 22q11.2 deletion and 17/39 did not have it; no patient had a 10p loss. Among the 22 deleted patients, 19 had congenital heart disease (mostly TOF). Twelve patients without deletion had heart defects such as TOF (4/12), isolate ventricular septal defect (2/12) or other disorders (6/12). CONCLUSION: In our small sample about ~56% of the patients, regardless of the clinical diagnosis, had the expected 22q11.2 deletion. We remark the importance of early cytogenetic diagnosis in order to achieve a proper integral management of the patients and their families.

INTRODUCCIÓN: La deleción 22q11.2 ocurre con una frecuencia de 1:4,000-1:6,000 nacidos vivos, mientras que la deleción 10p13p14 es detectada en 1:200,000 recién nacidos. Ambas deleciones comparten características clínicas similares tales como defectos cardiacos congénitos y anomalías inmunológicas. OBJETIVO: Identificar la deleción 22q11.2 en pacientes mexicanos con dismorfismo craneofacial sugestivo de síndrome DiGeorge o velocardiofacial y por lo menos con una característica clínica mayor (anomalía cardiaca, deficiencia inmunológica, defectos en paladar o retardo en el desarrollo). MÉTODOS: Estudio prospectivo de 39 pacientes captados entre 2012-2015 en el Instituto Mexicano del Seguro Social en Guadalajara, México. Los pacientes con características clínicas sugerentes de síndrome velocardiofacial o diagnostico confirmado de tetralogía de Fallot (TOF) o cardiopatía compleja fueron estudiados por bandas G y por hibridación in situ fluorescente (FISH) con una sonda dual TUPLE1(HIRA)/ARSA o TUPLE1(22q11)/22q13(SHANK3), seis pacientes sin la deleción 22q11.2 (seleccionados arbitrariamente) fueron estudiados con la sonda dual DiGeorge II (10p14)/D10Z1. RESULTADOS: Veintidós pacientes (7 hombres y 15 mujeres) tuvieron la deleción 22q11.2 y 17/39 no la tuvieron, ningún paciente tuvo la pérdida de 10p. Entre los 22 pacientes delecionados, 19 tuvieron defecto cardiaco congénito (principalmente TOF). Doce pacientes sin la deleción tuvieron defectos cardiacos congénitos como TOF (4/12), defecto del septo ventricular aislado (2/12) y otros trastornos cardiacos (6/12). CONCLUSIÓN: En nuestra pequeña muestra, alrededor de ~56% de los pacientes, independientemente de su diagnostico clínico, tuvieron la deleción 22q11.2 esperada. Resaltamos la importancia del diagnóstico citogenético temprano para determinar un apropiado manejo integral para el paciente y sus familiares.

22q11.2 deletion detected by in situ hybridization in Mexican patients with velocardiofacial syndrome-like features / Deleción 22q11.2 detectada por hibridación in situ en pacientes mexicanos con características clínicas similares al síndrome velocardiofacial

Abstract Introduction: Deletion 22q11.2 occurs in 1:4,000-1:6,000 live births while 10p13p14 deletion is found in 1:200,000 newborns. Both deletions have similar clinical features such as congenital heart disease and immunological anomalies. Objective: We looked for a 22q11.2 deletion in Mexican patients with craniofacial dysmorphisms suggestive of DiGeorge or velocardiofacial syndromes and at least one major phenotypic feature (cardiac anomaly, immune deficiency, palatal defects or development delay). Methods: A prospective study of 39 patients recruited in 2012-2015 at the Instituto Mexicano del Seguro Social at Guadalajara, Mexico. The patients with velocardiofacial syndrome-like features or a confirmed tetralogy of Fallot (TOF) or complex cardiopathy were studied by G-banding and fluorescence in situ hybridization (FISH) with a dual TUPLE1(HIRA)/ARSA or TUPLE1(22q11)/22q13(SHANK3) probe, six patients without the 22q11.2 deletion (arbitrarily selected) were tested with the dual DiGeorge II (10p14)/D10Z1 probe. Results: Twenty-two patients (7 males and 15 females) had the 22q11.2 deletion and 17/39 did not have it; no patient had a 10p loss. Among the 22 deleted patients, 19 had congenital heart disease (mostly TOF). Twelve patients without deletion had heart defects such as TOF (4/12), isolate ventricular septal defect (2/12) or other disorders (6/12). Conclusion: In our small sample about ~56% of the patients, regardless of the clinical diagnosis, had the expected 22q11.2 deletion. We remark the importance of early cytogenetic diagnosis in order to achieve a proper integral management of the patients and their families.

Resumen Introducción: La deleción 22q11.2 ocurre con una frecuencia de 1:4,000-1:6,000 nacidos vivos, mientras que la deleción 10p13p14 es detectada en 1:200,000 recién nacidos. Ambas deleciones comparten características clínicas similares tales como defectos cardiacos congénitos y anomalías inmunológicas. Objetivo: Identificar la deleción 22q11.2 en pacientes mexicanos con dismorfismo craneofacial sugestivo de síndrome DiGeorge o velocardiofacial y por lo menos con una característica clínica mayor (anomalía cardiaca, deficiencia inmunológica, defectos en paladar o retardo en el desarrollo) Métodos: Estudio prospectivo de 39 pacientes captados entre 2012-2015 en el Instituto Mexicano del Seguro Social en Guadalajara, México. Los pacientes con características clínicas sugerentes de síndrome velocardiofacial o diagnostico confirmado de tetralogía de Fallot (TOF) o cardiopatía compleja fueron estudiados por bandas G y por hibridación in situ fluorescente (FISH) con una sonda dual TUPLE1(HIRA)/ARSA o TUPLE1(22q11)/22q13(SHANK3), seis pacientes sin la deleción 22q11.2 (seleccionados arbitrariamente) fueron estudiados con la sonda dual DiGeorge II (10p14)/D10Z1. Resultados: Veintidós pacientes (7 hombres y 15 mujeres) tuvieron la deleción 22q11.2 y 17/39 no la tuvieron, ningún paciente tuvo la pérdida de 10p. Entre los 22 pacientes delecionados, 19 tuvieron defecto cardiaco congénito (principalmente TOF). Doce pacientes sin la deleción tuvieron defectos cardiacos congénitos como TOF (4/12), defecto del septo ventricular aislado (2/12) y otros trastornos cardiacos (6/12). Conclusión: En nuestra pequeña muestra, alrededor de ~56% de los pacientes, independientemente de su diagnostico clínico, tuvieron la deleción 22q11.2 esperada. Resaltamos la importancia del diagnóstico citogenético temprano para determinar un apropiado manejo integral para el paciente y sus familiares.