Scientific Letter
Phenotype variability in thirteen 16p11.2 deletion patients
Variabilidad fenotípica en 13 casos de deleción 16p11.2
a Unidad de Genética Clínica, Servicio de Pediatría, Hospital de Sabadell, Corporació Sanitària Parc Taulí, Fundació Parc Taulí Institut Universitari UAB, Sabadell, Spain
b Laboratorio de Genética, UDIAT-Centre Diagnòstic Hospital de Sabadell, Corporació Sanitària Parc Taulí, Fundació Parc Taulí Institut Universitari UAB, Sabadell, Spain
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"etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Elisabeth" "apellidos" => "Gabau" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Neus" "apellidos" => "Baena" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Miriam" "apellidos" => "Guitart" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Genética Clínica, Servicio de Pediatría, Hospital de Sabadell, Corporació Sanitària Parc Taulí, Fundació Parc Taulí Institut Universitari UAB, Sabadell, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Laboratorio de Genética, UDIAT-Centre Diagnòstic Hospital de Sabadell, Corporació Sanitària Parc Taulí, Fundació Parc Taulí Institut Universitari UAB, Sabadell, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Variabilidad fenotípica en 13 casos de deleción 16p11.2" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In the past 10 years, comparative genomic hybridization array (aCGH) methods have allowed the identification and characterization of numerous syndromes caused by copy-number variations. The deletion of approximately 600<span class="elsevierStyleHsp" style=""></span>kb in chromosome 16p11.2 is one of the most frequent disorders of this type.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> It was initially associated with autism, but at present there is evidence of its association with a wide phenotypic spectrum with incomplete penetrance and variable expression, manifesting most frequently with language disorders, obesity and psychiatric disorders.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">2–4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Chromosome 16p11.2 deletion syndrome (OMIM 611913) has an autosomal dominant pattern of inheritance. Most cases correspond to <span class="elsevierStyleItalic">de novo</span> mutations, but the deletion can be inherited from a symptomatic or asymptomatic parent.</p><p id="par0015" class="elsevierStylePara elsevierViewall">We present 6 index cases (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) and the cases of 7 relatives with chromosome 16p11.2 deletion syndrome diagnosed by means of aCGH.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">We obtained the informed consent of all the patients or their legal guardians.</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 1</span>. Boy aged 7 years presenting with psychomotor retardation (PMR), social impairment and nasal flaring. In the past few months, the patient had exhibited spells during which he was unaware of his surroundings during the evaluation. The mother was a carrier of the deletion and reported having had problems in school and dropping out of compulsory secondary education.</p><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 2</span>. Boy aged 6 years with language delay, mainly in expressive language, and difficulty performing logical or sequential tasks. The mother, grandmother and 3 maternal uncles had the deletion.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The grandmother, aged 53 years, had epilepsy and overweight. The mother, aged 33 years, had anxiety and depression. A maternal aunt aged 27 years dropped out of compulsory education due to school failure. She had a history of morbid obesity but had lost weight as a result of anxiety and depression. A maternal uncle aged 16 years was obese and had no problems in school. The other uncle, aged 12 years, was receiving treatment for ADHD, had unilateral duplex kidney, 2 hemivertebrae, and academic difficulties on account of which he required adaptations to the regular curriculum. All family members had undergone adenotonsillectomy.</p><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 3</span>. Boy aged 8 years that presented with PMR and difficulties with expressive language and writing.</p><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 4</span>. Girl aged 11 years that presented with PMR, absence seizures with onset at age 18 months, expressive language disorder and polyphagia requiring monitoring to maintain an adequate weight.</p><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 5</span>. Girl aged 15 years with intellectual disability (ID), epilepsy and obesity. The aCGH evaluation also detected a 1 Mb deletion in chromosome 14q11.2 classified as a variant of unknown significance. Her mother carried the 16p11.2 deletion and was overweight.</p><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 6</span>. Woman aged 26 years. She had been evaluated as early as age 4 months for assessment of macrocephaly with a head circumference of 46<span class="elsevierStyleHsp" style=""></span>cm (<span class="elsevierStyleItalic">z</span>-score, +4.4). She had moderate hydrocephalus that resolved spontaneously by age 4 years. From age 5 months to 3 years she had partial epilepsy of infancy, with no seizures after that age. She exhibited clear problems with language starting at age 3 years. The patient has had depression and bulimia as an adult. She was unable to graduate from high school. Her mother and siblings did not carry the deletion, and the father was not available for assessment.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The typical 16p11.2 deletion was first described in 2007 and encompasses 29 genes. The main reasons that lead to evaluation are ID, PMR and autism. In our series, the most frequent reason for evaluation was ID.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The clinical picture is variable. This deletion should be suspected in children with delayed language development with abnormal speech articulation, ID, social impairments, macrocephaly, seizures, vertebral malformations and/or Chiari malformation and obesity in the context of PMR.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Intellectual disability is usually mild (<span class="elsevierStyleSmallCaps">IQ,</span> 82.7), but with IQ scores nearly 2 SDs below those of non-carrier familial controls.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> Twenty-four percent have autism spectrum disorder (ASD), but up to 70% present with autism traits, such as repetitive behaviours. Cases 1, 2 and 5 in our series had autistic traits, but did not fulfil the criteria for diagnosis of ASD. Language disorders are present in 70% of affected individuals, and there seem to be anatomical abnormalities associated to problems in different areas of language development.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">5,6</span></a> In our case series, language disorders were the most frequent feature along with mild ID.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Ninety-three percent of adults with 16p11.2 deletion syndrome have at least one diagnosed psychiatric disorder; in our series, 3 out of 5 adults with the deletion had psychiatric disorders.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Seizures, described in 20% of patients in the literature, occurred in 4 of the index cases. Only one patient had macrocephaly, and only one relative of an index case had a vertebral malformation.</p><p id="par0085" class="elsevierStylePara elsevierViewall">The management of chromosome 16p11.2 deletion syndrome should focus on the specific clinical manifestations presented by the patient. Early diagnosis helps identify the potential needs of patients, such as early stimulation, speech therapy and dietary management, thus leading to improved outcomes. It also makes genetic counselling possible.</p><p id="par0090" class="elsevierStylePara elsevierViewall">In conclusion, chromosome 16p11.2 deletion syndrome is characterized by a wide phenotypic variability between individuals and within families, and the most frequent manifestations are language disorders, mild ID, mild dysmorphic features and obesity. Considering that this microdeletion can be inherited, we recommend genetic testing of individuals with compatible manifestations for the purpose of early intervention and genetic counselling.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Rodà D, Gabau E, Baena N, Guitart M. Variabilidad fenotípica en 13 casos de deleción 16p11.2. An Pediatr (Barc). 2018;89:62–63.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">+: present; −: absent; ADHD, attention-deficit hyperactivity disorder; AT, adenotonsillectomy; BMI, body mass index; F, female; HC, head circumference; HPS, hypertrophic pyloric stenosis; Ht, height; IUGR, intrauterine growth restriction; M, male; NR, not reported; PCTL, percentile; SAHS, sleep apnoea hypopnoea syndrome; TTN, transitory tachypnoea of the newborn; Wt, weight; VOUS, variant of unknown significance.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case 1 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case 2 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case 3 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case 4 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case 5 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case 6 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sex, age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M, 7 y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M, 6 y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M, 8 y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F, 11 y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F, 15 y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F, 26 y \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Size of deletion (number of contained genes) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">596<span class="elsevierStyleHsp" style=""></span>kb (29) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">598<span class="elsevierStyleHsp" style=""></span>kb (29) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">448<span class="elsevierStyleHsp" style=""></span>kb (26) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">516<span class="elsevierStyleHsp" style=""></span>kb (28) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">514<span class="elsevierStyleHsp" style=""></span>kb (27) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">552<span class="elsevierStyleHsp" style=""></span>kb (29) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Inheritance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Maternal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Maternal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">de novo</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">de novo</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Maternal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Undetermined<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Perinatal history \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Delivery at 36 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IUGR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TTN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anthropometry<br>Wt (kg)<br>Ht and HC (cm)<br>BMI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wt: 33 (82th PCTL)<br>Ht: 124 (15th PCTL)<br>HC: 54 (83th PCTL)<br>BMI: 21.5 (96th PCTL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wt: 32.5 (97th PCTL)<br>Ht: 120 (45th PCTL)<br>HC: 54 (92th PCTL)<br>BMI: 22.6 (>99th PCTL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wt: 46.5 (98th PCTL)<br>Ht: 130 (31th PCTL)<br>HC: 55 (94th PCTL)<br>BMI: 27.5 (>99th PCTL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wt: 41.5 (42th PCTL)<br>Ht: 149 (47th PCTL)<br>HC: 55 (70th PCTL)<br>BMI: 18.9 (43th PCTL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wt: 63 (74th PCTL)<br>Ht: 158 (26th PCTL)<br>HC: 55 (88th PCTL)<br>BMI: 25.3 (88th PCTL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wt: >100 (>99th PCTL)<br>Ht: 159 (20th PCTL)<br>HC: 58 (>98th PCTL)<br>BMI >39.6 (>99th PCTL) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dysmorphic features \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cupid's bow upper lip, macroglossia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cupid's bow upper lip, single palmar crease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High-arched palate, clinodactyly in 5th finger \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cupid's bow upper lip, high-arched palate, short neck \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High-arched palate, short neck \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Psychomotor retardation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (mild) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (mild) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (mild) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cognitive impairment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (mild) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (borderline) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (mild) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (mild) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (mild) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (mild) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Social impairment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Language disorder \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Behavioural/psychiatric disorder \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ADHD<br>Self-harm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Depression<br>Bulimia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Epilepsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (resolved) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Macrocephaly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Obesity (years of age at onset) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Overweight \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Strabismus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SAHS<br>AT<br>Submucous cleft palate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypotonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Spina bifida occulta<br>Pes cavus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VOUS at 14q11.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HPS<br>Hydrocephalus<br>SAHS<br>AT \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1817930.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Father not available.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical characteristics of index cases.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0035" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.B. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 2 | 8 |
| 2024 October | 57 | 40 | 97 |
| 2024 September | 59 | 22 | 81 |
| 2024 August | 52 | 47 | 99 |
| 2024 July | 82 | 27 | 109 |
| 2024 June | 84 | 37 | 121 |
| 2024 May | 61 | 33 | 94 |
| 2024 April | 82 | 38 | 120 |
| 2024 March | 54 | 24 | 78 |
| 2024 February | 83 | 35 | 118 |
| 2024 January | 59 | 21 | 80 |
| 2023 December | 60 | 26 | 86 |
| 2023 November | 56 | 25 | 81 |
| 2023 October | 55 | 19 | 74 |
| 2023 September | 51 | 25 | 76 |
| 2023 August | 50 | 13 | 63 |
| 2023 July | 63 | 24 | 87 |
| 2023 June | 52 | 20 | 72 |
| 2023 May | 76 | 27 | 103 |
| 2023 April | 24 | 10 | 34 |
| 2023 March | 68 | 23 | 91 |
| 2023 February | 61 | 20 | 81 |
| 2023 January | 48 | 19 | 67 |
| 2022 December | 65 | 23 | 88 |
| 2022 November | 89 | 43 | 132 |
| 2022 October | 126 | 33 | 159 |
| 2022 September | 45 | 25 | 70 |
| 2022 August | 78 | 45 | 123 |
| 2022 July | 64 | 41 | 105 |
| 2022 June | 80 | 47 | 127 |
| 2022 May | 93 | 31 | 124 |
| 2022 April | 125 | 29 | 154 |
| 2022 March | 128 | 49 | 177 |
| 2022 February | 106 | 36 | 142 |
| 2022 January | 105 | 39 | 144 |
| 2021 December | 85 | 45 | 130 |
| 2021 November | 92 | 43 | 135 |
| 2021 October | 82 | 76 | 158 |
| 2021 September | 80 | 39 | 119 |
| 2021 August | 69 | 41 | 110 |
| 2021 July | 133 | 35 | 168 |
| 2021 June | 98 | 41 | 139 |
| 2021 May | 85 | 77 | 162 |
| 2021 April | 150 | 76 | 226 |
| 2021 March | 97 | 39 | 136 |
| 2021 February | 68 | 25 | 93 |
| 2021 January | 77 | 22 | 99 |
| 2020 December | 61 | 26 | 87 |
| 2020 November | 96 | 24 | 120 |
| 2020 October | 69 | 28 | 97 |
| 2020 September | 44 | 28 | 72 |
| 2020 August | 57 | 28 | 85 |
| 2020 July | 40 | 30 | 70 |
| 2020 June | 42 | 24 | 66 |
| 2020 May | 59 | 43 | 102 |
| 2020 April | 31 | 16 | 47 |
| 2020 March | 59 | 16 | 75 |
| 2020 February | 38 | 13 | 51 |
| 2020 January | 40 | 15 | 55 |
| 2019 December | 45 | 17 | 62 |
| 2019 November | 49 | 16 | 65 |
| 2019 October | 53 | 20 | 73 |
| 2019 September | 45 | 24 | 69 |
| 2019 August | 31 | 19 | 50 |
| 2019 July | 38 | 20 | 58 |
| 2019 June | 27 | 27 | 54 |
| 2019 May | 42 | 24 | 66 |
| 2019 April | 59 | 26 | 85 |
| 2019 March | 27 | 20 | 47 |
| 2019 February | 51 | 22 | 73 |
| 2019 January | 33 | 16 | 49 |
| 2018 December | 48 | 34 | 82 |
| 2018 November | 56 | 24 | 80 |
| 2018 October | 50 | 21 | 71 |
| 2018 September | 49 | 49 | 98 |
| 2018 June | 0 | 5 | 5 |
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