Table 2 Probands with diagnostic exome sequencing result following data reanalysis
Pt. no. | Sex/ age (year) | Clinical symptoms reported to external lab | No. persons sequenced | Causative gene/variant | Dx. (OMIM number) | Inheritance | Date first lab report/data variant published in database or PubMed | Date gene–disease association published | Variant suggested by lab | Explanation of external laboratory | Reason for the negative exome result |
|---|---|---|---|---|---|---|---|---|---|---|---|
1 | F/ 2.5 | Pruritus, cholestasis, normal GGT and alkaline phosphatase, liver biopsy with mild fibrosis, high serum bile salts | Trio | SLC10A1,NM003049.3:c.601 611del,NP 003040.1:p.Ala201SerfsTer73 (LP) and c.745C>T,NP 003040.1:p.Arg249Trp (U) | NTCP deficiency (none) | AR compound heterozygote | 6 December 2016/8 March 2017 for c.745C>T (U in ClinVar) | 2 September 2014 | Heterozygous variant in ABCB4 | Both variants observed in our data; finding still not considered diagnostic, but rather a research finding | Lacking information on gene–phenotype association in OMIM |
2 | M/2.2 | Delayed motor milestones, delayed speech, dysmorphic features, hypotonia, hyperreflexia | Trio | GNB1, NM 001282539.1:c.158G>A,NP 001269468.1:p.Gly53Glu (LP) | MR, AD, 42 (616973) | AD de novo | 27 October 2016/none | 5 May 2016 | None | Causal role of GNB1 not fully established at the time of the report | No explanation |
3 | M/1.1 | Hypotonia, motor DD and nystagmus (improved over time), frontal bossing and bitemporal narrowing; family history positive for atrial septal defect, hemophilia and bilateral club foot | Trio | ITPR1, NM 001099952.2:c.1252–2A>T (P) | Gillespie syndrome (206700) | AD de novo | 28 December 2016/none | 17 September 2012 | Homozygous variant in LAMA1 | The mentioned de novo variant was identified but the variant was of low quality and was interpreted as a potential artifact | Variant considered a technical artifact |
4 | M/0.2 | Microcephaly, hypotonia, severe global developmental seizures | Single | MECP2, NM 004992.3:c.905C>T, NP 004983.1:p.Pro302Leu (P) | Encephalopathy, neonatal severe, due to MECP2 variants (300673) | X-linked de novo | 28 December 2015/30 Jun 2015 reported as likely pathogenic in ClinVar | 12 June 2001 | Homozygous variant in TUBGCP4 | Mostly seeking homozygous variants due to consanguinity | Incorrect interpretation of mode of inheritance |
5 | M/2.9 | ASD, VSD, retinal coloboma, epilepsy, small hippocampus, generalized seizures, dysmorphic facial features, FTT | Trio | HNRNPU, NM 004501.3:c.1173+5G>A (LP) | Epileptic encephalopathy early infantile, 54 (61739) | AD de novo, proven abnormal splicing by RNA studies | 30 January 2017/none | 26 May 2013 | None | Gene was unrelated to any human disease in OMIM so focus was on high-impact variants. For HNRNPU, info did not suggest a specific human disease (biological process: circadian regulation of gene expression, negative regulation of telomere maintenance via telomerase, etc.) | Lacking information on gene–phenotype association in OMIM |
6 | M/6.0 | Macrocephaly, seizures, spasticity, impaired hearing, abnormal facial shape, hydronephrosis, maternal uncle with intellectual disability without epilepsy or spasticity | Trio | NFIA, NM 001134673.3:c.373A>G,NP 001128145.1:p.Lys125Glu (LP) | Brain malformations with or without urinary tract defects (613735) | AD de novo | 29 July 2015/none | 22 January 2014 | Hemizygous variant in OFD1 | Variant was identified at analysis, but no phenotype was attached to the gene, so it was not included in the report. Involvement of NFIA variant is now supported by the recent publication. Supportive information was not available at the time of reporting | Most relevant publications not in OMIM |
7 | M/0.9 | Muscular weakness, developmental hip dislocation, VSD, FTT, inguinal hernia; mother with autism, father with short stature, osteopenia, and osteoporosis | Trio | FOXP2, NM 001172766.2:c.1423C>T,NP 001166237.1:p.Arg475Ter (P), hyperlaxity not solved | Speech–language disorder, 1 (602081) | AD, inherited from mother with autism | 6 February 2018/none | 22 April 2005 | Homozygous variant in B4GAT1 | Controversial case with 3 different phenotypes described in the family (father and other relatives, mother and index); we did not report the heterozygous FOXP2 variant present in the index and mother, likely due to the lack of global DD in the index pt. at the time of analysis | Incorrect interpretation of the clinical context |
8 | M/ fetus | Termination of pregnancy product: cystic hygroma, head hyperextension, possible micrognathia, severely deformed lower legs (tibia/fibula), malformed thorax with echogenic angulated ribs; ongoing pregnancy: fetus with cystic hygroma only, suspected limb deformations not confirmed on subsequent fetal US | Quatro | SOX9, NM 000346.3:c.491A>C,NP 000337.1:p.Gln164Pro (P) | Campomelic dysplasia (114290) | AD de novo | 4 May 2018/none | 8 December 1994 | None | Variant in SOX9 was not present in the fetus (ongoing pregnancy), only in the sibling. It was not reported as it is a weak VUS, in silico predictions are benign in 2/4 tools used in-house, and it is missense with low Grantham distance. It was also not segregating with the disease in the family. In this case, 1 fetus was TOP and another ongoing, which means we are reporting only variants with class 1 or class 2 | Incorrect interpretation of the clinical context |
9 | F/3.1 | Macrocephaly, frontal bossing, delayed closure of fontanelles, depressed metopic ridge, hypertelorism, epicanthus inversus, 3 cafe au lait spots | Trio | MID1, NM_000381:exon10:c.1917delC:p.P639fs (P) | Opitz G/BBB syndrome (300000) | X-linked de novo | 5 February 2016 /none | 17 November 1997 | None | Variant in MID1 was detected but not considered related to the phenotype (as this is an X-linked condition in a female) | Incorrect interpretation of the clinical context |
10 | M/9 | Hearing loss, intellectual disability, sinusitis, macrocephaly, small cerebellum, clumsiness, diarrhea, increased 3-hydroxy-butyrylcarnitine | Single | GIPC3, NM 133261.2:c.937T>C,NP 573568.1:p.Ter313GlnextTer98 (as an explanation for hearing loss only) (LP) | Deafness, AR, 15 (601869) | AR, homozygous | 27 November 2017/none | 15 February 2011 | Homozygous variant in POLE | This case presented with a complex neurological phenotype with deafness as part of it; the GIPC3 was considered to explain a very small part of the phenotype and thus, it was not reported | Incorrect interpretation of the clinical context |
11 | F/19 | Microcephaly, retinitis pigmentosa, short stature, cataract, IgA nephropathy muscle cramps, intermittent elevated CPK | Trio | POC5, NM 001099271.1:c.304 305del,NP 001092741.1:p.Asp102Ter (U) | Retinitis pigmentosa (none) | AR, homozygous | 7 August 2015/none | 15 February 2018 | Compound heterozygous variants in ABCA4 | NR | |
12 | M/0.3 | Abnormal movements, seizures, severe hypotonia, cortical blindness, hypothermia, pale optic discs, encephalopathy | Trio | GABRA2, NM 000807.2:c.1003A>C,NP 000798.2:p.Asn335His (U) | Epileptic encephalopathy (none) | AD de novo | 16 August 2016/none | 22 May 2018 | None | NR | |
13 | M/2 | Hepatospleno-megaly, global DD, FTT, microcephaly, dysmorphic features, SNHL, cerebral visual disturbances | Trio | C19orf70, NM 001308240.1:c.110del,NP 001295169.1:p.Gly37GlufsTer75 (U) | Mitochondrial hepato-encephalopathy (none) | AR | 27 April 2016/none | 3 August 2016 | None | NR |
