Table 1.
Summary of genetic results from second‐tier testing
| Fam | Age (years) Gender Parental consanguinity? | Phenotype (seizure onset and type(s); EEG semiology; developmental and neurological features) | Method Diagnosis | ACMG Classification Previously reported (PMID) | Variant (s) GRCh37 | Clinical utility of result |
|---|---|---|---|---|---|---|
| 1 |
11 female NC. |
Seizure onset 4 mo: IS + MF/tonic EEG: MFE +AB. Profound DD, dystonia, cortical inattention, slowly deteriorating course. |
Trio ES |
LP Yes (PMID: 10888601) |
NM_000026.2 (ADSL): c.[1288G>A]; [1370T>C] |
Palliative care initiated. No further intensive care admissions. Family closure. End diagnostic odyssey. |
| 2 |
11 male NC |
Seizure onset 4 mo: Tonic, CP, GTC + focal EEG: MFE + AB Profound DD, regression, hypotonia, progressive postnatal microcephaly and cerebral atrophy. |
Trio ES |
P Yes (PMID: 26318253) |
NM_183356.3
(ASNS): c.[866G>C]; [1010C>T] |
Reduced invasive/costly diagnostic investigations. Family closure. End diagnostic odyssey. |
| 3 |
1 female C (deceased) |
Seizure onset 4 mo: focal to intractable MF. EEG: modified hyps, MFE + AB Profound DD, regression, congenital retinopathy. |
Trio ES |
LP Yes (PMID: 27270415) |
NM_022786.1
(ARV1): c.[294 + 1G>A]; c.[294 + 1G>A] |
Reproductive planning (PGD) Family closure. |
| 4 |
14 female C. |
Seizure onset 5 mo: GTC, myoclonic, tonic EEG: GEA Profound DD, progressive postnatal microcephaly, mild cerebral atrophy. |
Trio ES |
P Yes (PMID 25411445) |
NM_016373.3
(WWOX): c.[140C>G]; [140C>G] |
Reproductive planning (for siblings) Family closure. End diagnostic odyssey. |
| 5 |
2 female NC. |
Neonatal seizure onset to intractable MF. EEG: MFE + AB. Profound DD. Profound hypotonia evolving to spastic quadriplegia; cortical inattention. |
Trio ES |
LP No |
NM_172107.2
(KCNQ2): c.[926C>T];[=] |
Family closure. |
| 6 |
13 female NC. |
Seizure onset 6 mo: IS to tonic and focal EEG: hyps. Profound DD, hyperkinesis. |
Trio ES |
P No |
NM_021007.2
(SCN2A): c.[680C>T];[=] |
Family closure. End diagnostic odyssey. |
| 7 |
4 female NC. |
Neonatal onset seizures: FD, tonic. EEG: MEA Moderate DD, hypotonia to hypertonia. |
Trio ES |
P Yes (ClinVar) |
NM_172107.2
(KCNQ2): c.740C>T; [=] |
Choice of AED therapy. Family closure. Family support group access. |
| 8 |
4 female NC (deceased). |
Neonatal onset seizures. Tonic. EEG: normal to MEA Severe DD and ASD. |
Trio ES |
LP No |
NM_021007.2
(SCN2A): c.[785T>C] |
Family closure. End diagnostic odyssey. Guidance on AED (favoring Na channel blockers) Guidance on health surveillance (counseling on increased risk SUDEP). |
| 9 |
1 male NC. |
Seizure onset 5 mo: IS to drop, atypical absences, tonic and nonconvulsive status. EEG modified hyps. ‐to GEA Profound DD, hypotonia and hyperkinesis. |
Trio ES |
LP Yes (PMID: 25262651) |
NM_004408.2
(DNM1): c.[709C>T];[=] |
Family closure. Reproductive planning. Support groups. Research cohort. End diagnostic odyssey. |
| 10 |
4 male NC. |
Seizure onset 3 mo: focal tonic/opisthotonic posturing. IS (6 mo) to multiple types. EEG: MEA +AB Severe DD, ASD, focal pachygyria. |
Trio ES |
LP Yes (PMID: 23603762) |
NM_001376.4
(DYNC1H1): c.[5884C>T];[=] |
Family information. Family closure. End diagnostic odyssey. |
| 11 |
5 male NC. |
Seizure onset 8 mo: myoclonic and focal EEG: MEA Severe DD, stereotypies, self‐injurious behaviors, ataxia. |
Trio ES |
P Yes |
NM_001008537.2 (KIAA2022): c.[1837G>T];[=] |
Family closure (parental guilt). Family planning. End diagnostic odyssey. Family information |
| 12 |
3 male NC. |
Antenatal fetal hiccoughs. Focal to IS (4 mo), tonic, myoclonic and atypical absences. EEG: MEA +AB; hyps. Profound DD, cortical atrophy, hypoplastic CC, hypotonia. |
Trio ES |
LP Yes (PMID: 29069600) |
NM_001287819.1 (KCNT2): c.[720T>A];[=] |
Family information. Reproductive planning. End diagnostic odyssey. Family closure. |
| 13 |
2 female NC. |
Seizure onset 4 mo: IS to multifocal seizures. EEG: modified hyps. to MEA +AB Severe DD, ASD. |
Trio ES |
P Yes (PMID: 23934111) |
NM_001099922.2 (ALG13): c.[320A>G];[=] |
End diagnostic odyssey. |
| 14 |
1 female NC (deceased) |
Antenatal fetal hiccoughs. Initial focal to IS (5 mo) to tonic + myoclonic. EEG: MEA + AB Profound DD, nystagmus. |
Trio ES |
P Yes (PMID: 23934111) |
NM_001099922.2 (ALG13): c.[320A>G];[=] |
Family closure. Reproductive planning. |
| 15 |
1 male NC |
Seizure onset 6 weeks: GTC and tonic EEG: normal to bitemporal EA Severe DD, hypotonia, strabismus. |
ST |
LP No |
NM_003159.2 (CDKL5): c.2420_2430delCCATTCATTCT |
Family closure (relieved parental guilt). End diagnostic odyssey. Targeted management. Parental information. |
| 16 |
2 male NC. |
Seizure onset 11 mo: IS EEG: hyps. Moderate DD. |
ST |
P Yes (PMID: 16650978) |
NM_139058.2
(ARX): c.[428_451dup] |
Reproductive planning (for immediate and extended family). End diagnostic odyssey. Family closure. Family information. |
AA, amino acid; AB, abnormal background; ACMG, American College of Medical Geneticists; AED, antiepileptic drug; ASD, autism spectrum disorder; B, benign; C, parental consanguinity; CC, corpus callosum; CP, cerebral palsy; D, damaging; DD, developmental delay; EA, epileptiform activity; EEG, electroencephalogram; ES, exome sequencing; FD, focal dyscognitive; GEA, generalized epileptiform activity; GTC, generalized tonic clonic; hyps., hypsarrhythmia; ID, intellectual disability; IS, infantile spasms; LP, likely pathogenic; MF, multifocal; MFE, multifocal epileptiform activity; mo, months; MRI, magnetic resonance imaging; NA, not applicable; NC, nonconsanguinity; P, pathogenic; PD, probably damaging; PGD, preimplantation genetic diagnosis; SUDEP, sudden unexpected death in epilepsy; ST, standard testing; T, tolerated.